Publications by authors named "Rastaldo Raffaella"

32 Publications

Advanced Nanotechnology for Enhancing Immune Checkpoint Blockade Therapy.

Nanomaterials (Basel) 2021 Mar 8;11(3). Epub 2021 Mar 8.

Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Italy.

Immune checkpoint receptor signaling pathways constitute a prominent class of "immune synapse," a cell-to-cell connection that represses T-lymphocyte effector functions. As a possible evolutionary countermeasure against autoimmunity, this strategy is aimed at lowering potential injury to uninfected cells in infected tissues and at minimizing systemic inflammation. Nevertheless, tumors can make use of these strategies to escape immune recognition, and consequently, such mechanisms represent chances for immunotherapy intervention. Recent years have witnessed the advance of pharmaceutical nanotechnology, or nanomedicine, as a possible strategy to ameliorate immunotherapy technical weaknesses thanks to its intrinsic biophysical properties and multifunctional modifying capability. To improve the long-lasting response rate of checkpoint blockade therapy, nanotechnology has been employed at first for the delivery of single checkpoint inhibitors. Further, while therapy via single immune checkpoint blockade determines resistance and a restricted period of response, strong interest has been raised to efficiently deliver immunomodulators targeting different inhibitory pathways or both inhibitory and costimulatory pathways. In this review, the partially explored promise in implementation of nanotechnology to improve the success of immune checkpoint therapy and solve the limitations of single immune checkpoint inhibitors is debated. We first present the fundamental elements of the immune checkpoint pathways and then outline recent promising results of immune checkpoint blockade therapy in combination with nanotechnology delivery systems.
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http://dx.doi.org/10.3390/nano11030661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998763PMC
March 2021

Nanoengineering in Cardiac Regeneration: Looking Back and Going Forward.

Nanomaterials (Basel) 2020 Aug 12;10(8). Epub 2020 Aug 12.

Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Torino, Italy.

To deliver on the promise of cardiac regeneration, an integration process between an emerging field, nanomedicine, and a more consolidated one, tissue engineering, has begun. Our work aims at summarizing some of the most relevant prevailing cases of nanotechnological approaches applied to tissue engineering with a specific interest in cardiac regenerative medicine, as well as delineating some of the most compelling forthcoming orientations. Specifically, this review starts with a brief statement on the relevant clinical need, and then debates how nanotechnology can be combined with tissue engineering in the scope of mimicking a complex tissue like the myocardium and its natural extracellular matrix (ECM). The interaction of relevant stem, precursor, and differentiated cardiac cells with nanoengineered scaffolds is thoroughly presented. Another correspondingly relevant area of experimental study enclosing both nanotechnology and cardiac regeneration, e.g., nanoparticle applications in cardiac tissue engineering, is also discussed.
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http://dx.doi.org/10.3390/nano10081587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466652PMC
August 2020

Dual Role of Autophagy in Regulation of Mesenchymal Stem Cell Senescence.

Front Cell Dev Biol 2020 24;8:276. Epub 2020 Apr 24.

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

During their development and overall life, mesenchymal stem cells (MSCs) encounter a plethora of internal and external stress signals and therefore, they need to put in action homeostatic changes in order to face these stresses. To this aim, similar to other mammalian cells, MSCs are endowed with two crucial biological responses, autophagy and senescence. Sharing of a number of stimuli like shrinkage of telomeres, oncogenic and oxidative stress, and DNA damage, suggest an intriguingly close relationship between autophagy and senescence. Autophagy is at first reported to suppress MSC senescence by clearing injured cytoplasmic organelles and impaired macromolecules, yet recent investigations also showed that autophagy can promote MSC senescence by inducing the production of senescence-associated secretory proteins (SASP). These apparently contrary contributions of autophagy may mirror an intricate image of autophagic regulation on MSC senescence. We here tackle the pro-senescence and anti-senescence roles of autophagy in MSCs while concentrating on some possible mechanistic explanations of such an intricate liaison. Clarifying the autophagy/senescence relationship in MSCs will help the development of more effective and safer therapeutic strategies.
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http://dx.doi.org/10.3389/fcell.2020.00276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193103PMC
April 2020

Cardioprotection of PLGA/gelatine cardiac patches functionalised with adenosine in a large animal model of ischaemia and reperfusion injury: A feasibility study.

J Tissue Eng Regen Med 2019 07 31;13(7):1253-1264. Epub 2019 May 31.

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

The protection from ischaemia-reperfusion-associated myocardial infarction worsening remains a big challenge. We produced a bioartificial 3D cardiac patch with cardioinductive properties on stem cells. Its multilayer structure was functionalised with clinically relevant doses of adenosine. We report here the first study on the potential of these cardiac patches in the controlled delivery of adenosine into the in vivo ischaemic-reperfused pig heart. A Fourier transform infrared chemical imaging approach allowed us to perform a characterisation, complementary to the histological and biochemical analyses on myocardial samples after in vivo patch implantation, increasing the number of investigations and results on the restricted number of pigs (n = 4) employed in this feasibility step. In vitro tests suggested that adenosine was completely released by a functionalised patch, a data that was confirmed in vivo after 24 hr from patch implantation. Moreover, the adenosine-loaded patch enabled a targeted delivery of the drug to the ischaemic-reperfused area of the heart, as highlighted by the activation of the pro-survival signalling reperfusion injury salvage kinases pathway. At 3 months, though limited to one animal, the used methods provided a picture of a tissue in dynamic conditions, associated to the biosynthesis of new collagen and to a non-fibrotic outcome of the healing process underway. The synergistic effect between the functionalised 3D cardiac patch and adenosine cardioprotection might represent a promising innovation in the treatment of reperfusion injury. As this is a feasibility study, the clinical implications of our findings will require further in vivo investigation on larger numbers of ischaemic-reperfused pig hearts.
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http://dx.doi.org/10.1002/term.2875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771506PMC
July 2019

Silica nanoparticles actively engage with mesenchymal stem cells in improving acute functional cardiac integration.

Nanomedicine (Lond) 2018 05 8;13(10):1121-1138. Epub 2018 Jun 8.

Department of Clinical & Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.

Aim: To assess functional effects of silica nanoparticles (SiO-NPs) on human mesenchymal stem cell (hMSC) cardiac integration potential.

Methods: SiO-NPs were synthesized and their internalization effects on hMSCs analyzed with particular emphasis on interaction of hMSCs with the cardiac environment Results: SiO-NP internalization affected the area and maturation level of hMSC focal adhesions, accounting for increased in vitro adhesion capacity and augmented engraftment in the myocardial tissue upon cell injection in infarcted isolated rat hearts. SiO-NP treatment also enhanced hMSC expression of Connexin-43, favoring hMSC interaction with cocultured cardiac myoblasts in an ischemia-like environment.

Conclusion: These findings provide strong evidence that SiO-NPs actively engage in mediating biological effects, ultimately resulting in augmented hMSC acute cardiac integration potential.
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http://dx.doi.org/10.2217/nnm-2017-0309DOI Listing
May 2018

Role of three adipokines in metabolic syndrome.

Pol Arch Med Wewn 2016 Apr 29;126(4):219-21. Epub 2016 Apr 29.

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http://dx.doi.org/10.20452/pamw.3386DOI Listing
April 2016

Effects of apelin on the cardiovascular system.

Heart Fail Rev 2015 Jul;20(4):505-18

Department of Neuroscience, University of Turin, C.so Raffaello 30, 10125, Turin, Italy.

Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterized by different numbers of amino acids. The number of amino acids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes in apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long-lasting (6 h) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling.
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http://dx.doi.org/10.1007/s10741-015-9475-xDOI Listing
July 2015

The effect of bioartificial constructs that mimic myocardial structure and biomechanical properties on stem cell commitment towards cardiac lineage.

Biomaterials 2014 Jan 4;35(1):92-104. Epub 2013 Oct 4.

Institute for Composite and Biomedical Materials, C.N.R., o.u. Pisa, Pisa, Italy. Electronic address:

Despite the enormous progress in the treatment of coronary artery diseases, they remain the most common cause of heart failure in the Western countries. New translational therapeutic approaches explore cardiomyogenic differentiation of various types of stem cells in combination with tissue-engineered scaffolds. In this study we fabricated PHBHV/gelatin constructs mimicking myocardial structural properties. Chemical structure and molecular interaction between material components induced specific properties to the substrate in terms of hydrophilicity degree, porosity and mechanical characteristics. Viability and proliferation assays demonstrated that these constructs allow adhesion and growth of mesenchymal stem cells (MSCs) and cardiac resident non myocytic cells (NMCs). Immunofluorescence analysis demonstrated that stem cells cultured on these constructs adopt a distribution mimicking the three-dimensional cell alignment of myocardium. qPCR and immunofluorescence analyses showed the ability of this construct to direct initial MSC and NMC lineage specification towards cardiomyogenesis: both MSCs and NMCs showed the expression of the cardiac transcription factor GATA-4, fundamental for early cardiac commitment. Moreover NMCs also acquired the expression of the cardiac transcription factors Nkx2.5 and TBX5 and produced sarcomeric proteins. This work may represent a new approach to induce both resident and non-resident stem cells to cardiac commitment in a 3-D structure, without using additional stimuli.
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http://dx.doi.org/10.1016/j.biomaterials.2013.09.058DOI Listing
January 2014

Balance of nitric oxide and reactive oxygen species in myocardial reperfusion injury and protection.

J Cardiovasc Pharmacol 2013 Dec;62(6):567-75

*Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, Orbassano, Italy; and †Department of Neuroscience, Physiology Division, University of Turin, Turin, Italy.

Depending on their concentrations, both nitric oxide (NO) and reactive oxygen species (ROS) take part either in myocardial ischemia reperfusion injury or in protection by ischemic and pharmacological preconditioning (Ipre) and postconditioning (Ipost). At the beginning of reperfusion, a transient release of NO is promptly scavenged by ROS to form the highly toxic peroxynitrite, which is responsible for a further increase of ROS through endothelial nitric oxide synthase uncoupling. The protective role of NO has suggested the use of NO donors to mimic Ipre and Ipost. However, NO donors have not always given the expected protection, possibly because they are responsible for the production of different amounts of ROS that depend on the amount of released NO. This review is focused on the role of the balance of NO and ROS in myocardial injury and its prevention by Ipre and Ipost and after the use of NO donors given with or without antioxidant compounds to mimic Ipre and Ipost.
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http://dx.doi.org/10.1097/FJC.0b013e3182a50c45DOI Listing
December 2013

A lipophilic nitric oxide donor and a lipophilic antioxidant compound protect rat heart against ischemia-reperfusion injury if given as hybrid molecule but not as a mixture.

J Cardiovasc Pharmacol 2012 Mar;59(3):241-8

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

Low concentrations of a hydrophilic nitric oxide donor (NOD) are reported to reduce myocardial reperfusion injury only when combined with a lipophilic antioxidant (AOX) to form a hybrid molecule (HYB). Here we tested whether liposoluble NOD requires to be combined with AOX to be protective. Isolated rat hearts underwent 30 minutes of ischemia and 120 minutes of reperfusion. To induce postconditioning, 1 μM solutions of the following liposoluble compounds were given during the first 20 minutes of reperfusion: NOD with weak (w-NOD) or strong NO-releasing potency (s-NOD); weak HYB built up with w-NOD and a per se ineffective AOX lead; strong HYB built up with s-NOD and the same AOX; mixtures of w-NOD plus AOX or s-NOD plus AOX. A significant reduction of infarct size with improved recovery of cardiac function was obtained only with weak HYB. We suggest that w-NOD requires the synergy with a per se ineffective AOX to protect. The synergy is possible only if the 2 moieties enter the cell simultaneously as a hybrid, but not as a mixture. It seems that strong HYB was ineffective because an excessive intracellular NO release produces a large amount of reactive species, as shown from the increased nitrotyrosine production.
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http://dx.doi.org/10.1097/FJC.0b013e31823d2dcaDOI Listing
March 2012

Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia.

Am J Physiol Heart Circ Physiol 2011 Jun 4;300(6):H2308-15. Epub 2011 Mar 4.

Dipartimento di Scienze Cliniche e Biologiche, Facoltà di Medicina e Chirurgia "S. Luigi Gonzaga", Regione Gonzole 10, 10043 Orbassano (TO) Italy.

We studied whether apelin-13 is cardioprotective against ischemia/reperfusion injury if given as either a pre- or postconditioning mimetic and whether the improved postischemic mechanical recovery induced by apelin-13 depends only on the reduced infarct size or also on a recovery of function of the viable myocardium. We also studied whether nitric oxide (NO) is involved in apelin-induced protection and whether the reported ischemia-induced overexpression of the apelin receptor (APJ) plays a role in cardioprotection. Langendorff-perfused rat hearts underwent 30 min of global ischemia and 120 min of reperfusion. Left ventricular pressure was recorded. Infarct size and lactate dehydrogenase release were determined to evaluate the severity of myocardial injury. Apelin-13 was infused at 0.5 μM concentration for 20 min either before ischemia or in early reperfusion, without and with NO synthase inhibition by N(G)-nitro-l-arginine (l-NNA). In additional experiments, before ischemia also 1 μM apelin-13 was tested. APJ protein level was measured before and after ischemia. Whereas before ischemia apelin-13 (0.5 and 1.0 μM) was ineffective, after ischemia it reduced infarct size from 54 ± 2% to 26 ± 4% of risk area (P < 0.001) and limited the postischemic myocardial contracture (P < 0.001). l-NNA alone increased postischemic myocardial contracture. This increase was attenuated by apelin-13, which, however, was unable to reduce infarct size. Ischemia increased APJ protein level after 15-min perfusion, i.e., after most of reperfusion injury has occurred. Apelin-13 protects the heart only if given after ischemia. In this protection NO plays an important role. Apelin-13 efficiency as postconditioning mimetic cannot be explained by the increased APJ level.
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http://dx.doi.org/10.1152/ajpheart.01177.2010DOI Listing
June 2011

Effect of apelin-apelin receptor system in postischaemic myocardial protection: a pharmacological postconditioning tool?

Antioxid Redox Signal 2011 Mar 30;14(5):909-22. Epub 2010 Nov 30.

Istituto Nazionale per la Ricerca Cardiovascolare, Bologna, Italy.

In the heart, a great part of ischaemia and reperfusion injuries occurs mainly during the first minutes of reperfusion. The opening of the mitochondrial permeability transition pores is the end point of the cascade to myocardial damage. Also, oxidative stress contributes to cell death. Postconditioning is a protective maneuver that can be selectively timed at the beginning of reperfusion. It is hypothesized that it acts via the reperfusion injury salvage kinase pathway, which includes nitric oxide-dependent and nitric oxide-independent cascades. Apelin is an endogenous peptide that can protect the heart from reperfusion injury if given at the beginning of reperfusion but not before ischaemia. It is hypothesized that it may trigger the reperfusion injury salvage kinase pathway via a specific apelin receptor. Apelin can also limit the oxidative stress by the activation of superoxide dismutase. Apelin and apelin receptor expression increase early after ischaemia and at the beginning of an ischaemic heart failure. These observations suggest that the endogenous release of the peptide can limit the severity of an infarction and ameliorate myocardial contractility compromised by the appearance of the failure. Due to its protective activities, apelin could be a therapeutic tool if administered with the same catheter used for angioplasty or after the maneuvers aimed at bypassing a coronary occlusion.
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http://dx.doi.org/10.1089/ars.2010.3355DOI Listing
March 2011

Effects of nitric oxide donor antioxidants containing the phenol vitamin E substructure and a furoxan moiety on ischemia/reperfusion injury.

Arzneimittelforschung 2009 ;59(3):111-6

Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Torino, Italy.

Nitric oxide (NO) donor antioxidants are a class of polyvalent drugs which is the focus of great interest today. They are potentially useful for the treatment of many forms of cardiovascular diseases, including the myocardial ischemia/reperfusion (I/R) damage which seems to be due to both a burst of reactive oxygen species (ROS) and a reduced release of NO during reperfusion. In this paper the results of a study on the ability of new NO-donor antioxidants containing the phenol vitamin E substructure and furoxan moiety to attenuate I/R damage are reported. The compounds under study are obtained by combining the phenol moiety (6-hydroxy-2,2,5,7,8-pentamethylchroman) present in vitamin E with differently substituted furoxan substructures endowed with different capacity of NO-release. Their antioxidant and NO-dependent vasodilator activities are reported. The I/R experiments were performed on isolated rat heart preparations perfused at a constant flow. After 20 min of stabilization, global ischemia was obtained by interrupting the perfusion for 30 min. After ischemia the hearts were reperfused for 2 h. The compounds were added to the perfusion buffer during the first 20 min of reperfusion. At the end of each experiment, the infarct size was measured with nitro-blue tetrazolium. From the results it appears that the limitation of the infarct area is favoured by an appropriate balance between NO-donor and antioxidant properties and that these two actions are synergic.
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http://dx.doi.org/10.1055/s-0031-1296372DOI Listing
June 2009

Cardioprotection: a radical view Free radicals in pre and postconditioning.

Biochim Biophys Acta 2009 Jul 24;1787(7):781-93. Epub 2009 Feb 24.

Dipartimento di Scienze Cliniche e Biologiche Università di Torino, Italy; Istituto Nazionale Ricerche Cardiovascolari, Bologna, Italy.

A series of brief (a few minutes) ischemia/reperfusion cycles (ischemic preconditioning, IP) limits myocardial injury produced by a subsequent prolonged period of coronary artery occlusion and reperfusion. Postconditioning (PostC), which is a series of brief (a few seconds) reperfusion/ischemia cycles at reperfusion onset, attenuates also ischemia/reperfusion injury. In recent years the main idea has been that reactive oxygen species (ROS) play an essential, though double-edged, role in cardioprotection: they may participate in reperfusion injury or may play a role as signaling elements of protection in the pre-ischemic phase. It has been demonstrated that preconditioning triggering is redox-sensitive, using either ROS scavengers or ROS generators. We have shown that nitroxyl triggers preconditioning via pro-oxidative, and/or nitrosative stress-related mechanism(s). Several metabolites, including acetylcholine, bradykinin, opioids and phenylephrine, trigger preconditioning-like protection via a mitochondrial K(ATP)-ROS-dependent mechanism. Intriguingly, and contradictory to the above mentioned theory of ROS as an obligatory part of reperfusion-induced damage, some studies suggest the possibility that some ROS at low concentrations could protect ischemic hearts against reperfusion injury. Yet, we demonstrated that ischemic PostC is also a cardioprotective phenomenon that requires the intervention of redox signaling to be protective. Emerging evidence suggests that in a preconditioning scenario a redox signal is required during the first few minutes of myocardial reperfusion following the index ischemic period. Intriguingly, the ROS signaling in the early reperfusion appear crucial to both preconditioning- and postconditioning-induced protection. Therefore, our and others' results suggest that the role of ROS in reperfusion may be reconsidered as they are not only deleterious.
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http://dx.doi.org/10.1016/j.bbabio.2009.02.008DOI Listing
July 2009

Postconditioning cardioprotection against infarct size and post-ischemic systolic dysfunction is influenced by gender.

Basic Res Cardiol 2009 Jul 22;104(4):390-402. Epub 2008 Nov 22.

Dip. to di Scienze Cliniche e Biologiche, Università di Torino, Regione Gonzole 10, 10043, Orbassano, TO, Italy.

Whether cardioprotection by postconditioning (PostC) is gender dependent is not clear. We studied the effect of PostC in terms of both infarct size (IS) and post-ischemic systolic dysfunction (PSD) reduction. Isolated male and female rat hearts were subjected to 10- or 30-min of global ischemia and 120-min of reperfusion, with or without PostC (i.e., 5 cycles of 10-s reperfusion/ischemia immediately after the ischemia). Surprisingly, after 10-min ischemia, IS and PSD were greater in female than male hearts (IS: 21 +/- 2% Vs. 11 +/- 2%; P < 0.01), while PostC attenuated IS and PSD in female hearts only. After 30-min ischemia IS was smaller in female than male hearts (52 +/- 2% Vs. 61 +/- 3%; P < 0.05), whereas PSD was similar in these two groups. PostC reduced IS in both genders, though the effect was smaller (P < 0.05) in females. Yet, PostC reduced PSD in female, but not in male hearts. Contracture development paralleled IS in all groups. To check the effects of buffer perfusion over heart function, additional hearts underwent 150-min buffer perfusion only. Contractile function of these hearts was not significantly affected over time. In conclusion IS, contracture and PSD are differently affected by gender, depending on ischemia duration. Yet, reduction of IS induced by PostC depends on the extension of IS induced by index-ischemia. While in female hearts reduction of PSD paralleled IS reduction, in male it does not occur. Results suggest that improvement of systolic function is mainly due to the anti-necrotic rather than to the anti-stunning effect exerted by PostC.
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http://dx.doi.org/10.1007/s00395-008-0762-8DOI Listing
July 2009

Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function.

Circ Res 2008 Jul 12;103(1):107-16. Epub 2008 Jun 12.

Department of Anesthesia and Division of Cardiology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. These alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. We tested whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by hepatocyte growth factor and insulin-like growth factor-1 invade the scarred myocardium and generate myocytes and coronary vessels improving the hemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful chemoattractant of CPCs, and insulin-like growth factor-1 promotes their proliferation and survival. Injection of CPCs or growth factors led to the replacement of approximately 42% of the scar with newly formed myocardium, attenuated ventricular dilation and prevented the chronic decline in function of the infarcted heart. Cardiac repair was mediated by the ability of CPCs to synthesize matrix metalloproteinases that degraded collagen proteins, forming tunnels within the fibrotic tissue during their migration across the scarred myocardium. New myocytes had a 2n karyotype and possessed 2 sex chromosomes, excluding cell fusion. Clinically, CPCs represent an ideal candidate cell for cardiac repair in patients with chronic heart failure. CPCs may be isolated from myocardial biopsies and, following their expansion in vitro, administered back to the same patients avoiding the adverse effects associated with the use of nonautologous cells. Alternatively, growth factors may be delivered locally to stimulate resident CPCs and promote myocardial regeneration. These forms of treatments could be repeated over time to reduce progressively tissue scarring and expand the working myocardium.
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http://dx.doi.org/10.1161/CIRCRESAHA.108.178525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747796PMC
July 2008

Omega 3 has a beneficial effect on ischemia/reperfusion injury, but cannot reverse the effect of stressful forced exercise.

Nutr Metab Cardiovasc Dis 2009 Jan 2;19(1):20-6. Epub 2008 May 2.

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Orbassano, Torino, Italy.

Background And Aim: The beneficial effects of exercise in reducing the incidence of cardiovascular diseases are well known. Several studies have demonstrated that forced exercise (FE) could activate a stress response similar to a restrain stress. Previous studies suggest that heart protection to ischemic events would be improved by an omega 3 free fatty acid (omega3-FFA)-enriched diet. Here, we investigate the impact of stressful FE and an omega 3-FFA-enriched diet on cardiac tolerance to ischemic events over one month.

Methods And Results: Twenty-four Wistar rats were randomly assigned to one of the following protocols: 1) Sedentary (SED) animals who were regularly fed; 2) sedentary animals who were given 1ml/day of fish oil for one month; 3) FE+omega3-FFA rats who were given 1ml/day of fish oil and forced to run on a motorized wheel for 30min every day, both for one month; and 4) FE animals were forced to exercise as group 3 and fed with a regular diet. At the end of the treatments an isolated heart preparation was performed. After a 30min global ischemic event and 2h reperfusion, hearts of sedentary-omega3 animals recovered about 37% of left ventricular developed pressure, whereas FE, omega3+FE and CTRL-SED animals recovered only about 15%, 5% and 8% respectively. Similarly, heart infarct size was significantly lower in sedentary-omega3 animals compared to animals in the three other groups.

Conclusions: Results indicate that one month of treatment with an omega3-FFA-enriched diet improves cardioprotection upon ischemic events, whereas FE leads to a reduced heart tolerance to ischemic events, which cannot be reversed by an omega3-FFA diet.
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http://dx.doi.org/10.1016/j.numecd.2008.01.004DOI Listing
January 2009

Early homing of adult mesenchymal stem cells in normal and infarcted isolated beating hearts.

J Cell Mol Med 2008 Apr;12(2):507-21

Department of Clinical and Biological Sciences, University of Turin, Italy.

Little is known on the early homing features of transplanted mesenchymal stem cells (MSCs). We used the isolated rat heart model to study the homing of MSCs injected in the ventricular wall of a beating heart. In this model all types of cells and matrix elements with their interactions are represented, while external interferences by endothelial/neutrophil interaction and neurohormonal factors are excluded. We studied the morphology and marker expression of MSCs implanted in normal hearts and in the border-zone of infarcted myocardium. Early morphological adaptation of MSC homing differs between normal and infarcted hearts over the first 6 hrs after transplantation. In normal hearts, MSCs migrate very early through the interstitial milieu and begin to show morphological changes. Yet, in infarcted hearts MSCs remain in the site of injection forming clusters of round-shaped cells in the border-zone of the infarcted area. Both in normal and infarcted hearts, immuno-histochemistry and confocal imaging showed that, besides the proliferative marker proliferating cell nuclear agent (PCNA), some transplanted cells early express myoblastic maker GATA-4, and some of them show a VWF immunopositivity. Moreover, a few hours after injection connexin-43 is well evident between cardiomyocytes and injected cells. This study indicates for the first time that the isolated beating heart is a good model to study early features of MSC homing without external interferences. The results show (i) that MSCs start to change marker expression few hours after injection into a beating heart and (ii) that infarcted myocardium influences transplanted MSC morphology and mobility within the heart.
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http://dx.doi.org/10.1111/j.1582-4934.2007.00121.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822539PMC
April 2008

Hyperoxia confers myocardial protection in mechanically ventilated rats through the generation of free radicals and opening of mitochondrial ATP-sensitive potassium channels.

Clin Exp Pharmacol Physiol 2008 Jan;35(1):64-71

Department of Emergency and Transplants, Section of Anaesthesia and Critical Care, University of Bari, Bari, Italy.

1. One hour exposure to hyperoxia has been shown previously to limit a subsequent ischaemia-reperfusion injury in spontaneously breathing rats. We tested the cardioprotective effect of a shorter period of hyperoxia during mechanical ventilation and the possible contribution of reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. 2. Mechanically ventilated rats were exposed to normoxia (Fi O2 = 0.3) or hyperoxia (Fi O2 = 1.0) for 30 min and pH, P CO2, PO2, heart rate, airway and blood pressure were measured at baseline and after 30 min mechanical ventilation. Isolated hearts were subsequently subjected to 30 min ischaemia and 120 min reperfusion. Infarct size and left ventricular end-diastolic pressure (LVEDP), developed pressure (LVDP) and coronary flow (CF) were measured. In order to investigate the role of ROS and KATP channels within the mechanism leading to cardioprotection, the free radical scavenger N-acetylcysteine (NAC; 150 mg/kg) was infused in mechanically ventilated rats and the KATP channel blockers glibenclamide (200 mmol/L) or 5-hydroxydecanoate (10 mmol/L) were infused in isolated hearts immediately before ischaemia. 3. No differences were detected in P CO2, pH, heart rate, airway and blood pressure between the groups. However, the PO2 in hyperoxic groups was significantly higher compared with that in normoxic groups (P < 0.01). After 30 min ischaemia, we found that hyperoxic preconditioning significantly improved CF (P < 0.01), LVDP (P < 0.01) and LVEDP (P < 0.01) and reduced the extent of infarct size in the reperfused heart compared with the normoxic group (P < 0.01). When rats were pretreated either with NAC before hyperoxic ventilation or with K(ATP) channel blockers before ischaemia, myocardial protection was abolished. 4. Hyperoxic mechanical ventilation, prior to ischaemia, reduces myocardial reperfusion injury. This is likely to occur through the induction of oxidative stress, which leads to myocyte mitoKATP channel opening.
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http://dx.doi.org/10.1111/j.1440-1681.2007.04745.xDOI Listing
January 2008

Human recombinant chromogranin A-derived vasostatin-1 mimics preconditioning via an adenosine/nitric oxide signaling mechanism.

Am J Physiol Heart Circ Physiol 2007 Jul 6;293(1):H719-27. Epub 2007 Apr 6.

Dipartimento di Neuroscienze, Sezione di Fisiologia, Università di Torino, Corso Raffaello 30, 10125 Turin, Italy.

The acidic protein chromogranin A (CgA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CgA NH(2)-terminal fragment STA-CgA(1-78) (hrSTA-CgA(1-78)), containing vasostatin-1 (CgA(1-76)) domain, exerts a negative inotropic effect and counteracts the beta-adrenergic positive inotropic effect on the rat heart. We hypothesized an involvement of nitric oxide (NO)-dependent pathway in both cardiodepression and cardioprotection by hrSTA-CgA(1-78). We also hypothesized an involvement of adenosine A(1) receptor and protein kinase C (PKC) in cardioprotection by hrSTA-CgA(1-78). Therefore, we evaluated whether 1) the cardioinhibition mediated by hrSTA-CgA(1-78) involves the G(i/o) proteins/NO-dependent signal transduction cascade, 2) hrSTA-CgA(1-78) induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of NO synthase (NOS), adenosine A(1) receptor, or PKC affects hrSTA-CgA(1-78) protection. Using the isolated rat heart, we found that the reduction of left ventricular pressure (LVP), rate-pressure product, and maximal values of the first derivative of LVP elicited by hrSTA-CgA(1-78) at 33 nM is abolished by blocking G(i/o) proteins with pertussis toxin, scavenging NO with hemoglobin, and blocking NOS activity with N(G)-monomethyl-l-arginine or N(5)-(iminoethyl)-l-ornithine, soluble guanylate cyclase with 1H-[1,2,4]oxadiazole-[4,4-a]quinoxalin-1-one, and protein kinase (PKG) with KT5823. Data suggest the involvement of the G(i/o) proteins/NO-cGMP-PKG pathway in the hrSTA-CgA(1-78)-dependent cardioinhibition. When given before 30 min of ischemia, hrSTA-CgA(1-78) significantly reduced the size of the infarct from 64 +/- 4 to 32 +/- 3% of the left ventricular mass. This protective effect was abolished by either NOS inhibition or PKC blockade and was attenuated, but not suppressed, by the blockade of A(1) receptors. These results suggest that hrSTA-CgA(1-78) activity triggers two different pathways: one of these pathways is mediated by A(1) receptors, and the other is mediated by NO release. As with repeated brief preconditioning ischemia, hrSTA-CgA(1-78) may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC.
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http://dx.doi.org/10.1152/ajpheart.01352.2006DOI Listing
July 2007

Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling.

Cardiovasc Res 2007 Jul 12;75(1):168-77. Epub 2007 Mar 12.

Dipartimento di Scienze Cliniche e Biologiche, dell'Università di Torino, Italy.

Objective: Postconditioning (PostC) maneuvers allow post-ischemic accumulation of autacoids, which trigger protection. We tested if PostC-triggering includes bradykinin (BK) B2 receptor activation and its downstream pathway.

Methods And Results: Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Infarct size was evaluated using nitro-blue tetrazolium staining. In Control hearts infarct size was 61+/-5% of risk area. PostC (5 cycles of 10 s reperfusion/ischemia) reduced infarct size to 22+/-4% (p<0.01). PostC protection was abolished by B2 BK receptor-antagonists (HOE140 or WIN64338), nitric oxide synthase-inhibitor (L-nitro-arginine-methylester), protein kinase G (PKG)-blocker (8-bromoguanosine-3',5'-cyclic-monophosphorothioate), and mitochondrial K(ATP) (mK(ATP))-blocker (5-hydroxydecanoate) each given for 3 min only. Since 3 min of BK-infusion (100 nM) did not reproduce PostC protection, protocols with Intermittent-BK infusion were used to mimic PostC: a) 5 cycles of 10 s oxygenated-no-BK/oxygenated+BK buffer; b) 5 cycles of 10 s oxygenated-no-BK/hypoxic+BK buffer. Both protocols with Intermittent-BK attenuated infarct size (36+/-5% and 38+/-4%, respectively; p<0.05 vs Control and NS vs PostC for both; NS vs each other). Intermittent-BK protection was abolished by the same antagonists used to prevent PostC protection. Intermittence of re-oxygenation only (5 cycles of 10 s oxygenated/hypoxic buffer) did not reproduce PostC. Yet, cardioprotection was triggered by intermittent mK(ATP) activation with diazoxide, but not by intermittent reactive oxygen species (ROS) generation with purine/xanthine oxidase. ROS scavengers (N-acetyl-L-cysteine or 2-mercaptopropionylglycine), given for 3 min only, abolished PostC-, Intermittent BK-and diazoxide-induced protection.

Conclusions: Intermittent targeting of specific cellular sites (i.e. BK B2 receptors and mK(ATP) channels) during early reperfusion triggers PostC protection via ROS signaling. Since neither intermittent oxygenation nor exogenous ROS generators can trigger protection, it is likely that intermittent autacoid accumulation and ROS compartmentalization may play a pivotal role in PostC-triggering.
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http://dx.doi.org/10.1016/j.cardiores.2007.03.001DOI Listing
July 2007

[Ischemic postconditioning: an effective strategy of myocardial protection?].

G Ital Cardiol (Rome) 2006 Jul;7(7):464-73

Sezione di Fisiologia, Dipartimento di Neuroscienze, Università degli Studi, Torino.

Post-ischemic reperfusion worsens myocardial injury. Ischemic preconditioning limits the damage by ischemia and reperfusion. Both adenosine and nitric oxide (NO) pathways are involved in protection. Preconditioning, however, is of little, if any, practical use as the onset of an infarction is usually unpredictable. Recently, it has been shown that the heart can be protected against the extension of reperfusion injuries if 3 or 4 brief (10-30 s) coronary occlusions are performed just at the beginning of the reperfusion. This procedure has been called post-conditioning. Post-conditioning reduces the oxidant-induced injury; moreover, it attenuates the local inflammatory response to reperfusion. Post-conditioning also activates triggers, signaling pathways and effectors implicated in other cardioprotective maneuvers, such as ischemic and pharmacological preconditioning. Post-conditioning seems to trigger the up-regulation of survival kinases principally known to attenuate the pathogenesis of apoptosis and possibly necrosis. As regards the possibility of pharmacological post-conditioning, several agents have been tested. We are testing NO donor(s), which can reduce infarct size in the rat in the absence of post-conditioning. Since during reperfusion there is a large production of reactive oxygen species, also the effect of administration of an antioxidant compound during reperfusion was studied. In the rat, such a procedure reduced the infarct size to a greater extent than post-conditioning. Moreover, an additive effect of NO donors and antioxidant compounds is possible.
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July 2006

Effect of endothelins on the cardiovascular system.

J Cardiovasc Med (Hagerstown) 2006 Sep;7(9):645-52

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

Endothelins (ETs) exert a persistent constrictor effect on the vessels via an increase in intracellular Ca2+ concentration due to the activation of Na+/H+ and Na+/Ca2+ exchangers of the vascular smooth muscle fibres. They also produce a transient dilator effect via the activation of endothelial nitric oxide synthase mediated by protein kinase B/Akt. ETA and ETB2 receptors are involved in vasoconstriction, whereas transient vasodilatation depends on the activation of ETB1 receptors. Depending on animal species and experimental conditions, ETs can also play a role in cardiac muscle contraction and induce either an increase or a decrease in contractility. It is likely that only ETA, and not ETB, receptors are involved in the ET-induced increase in myocardial contractility. As in the case of vasoconstriction, this inotropic effect depends on an increase in intracellular Ca2+ concentration induced by Na+/H+ and Na+/Ca2+ exchangers. Activation of the Na+/H+ exchanger is stimulated by protein kinase C, which is activated by diacylglycerol released in response to ET activity. It has also been proposed that the positive inotropic effect can occur without the contribution of the Na+/Ca2+ exchanger, if the cell alkalinisation produced by the Na/H exchanger improves myofibrillar Ca2+ sensitivity. A reduction in contractility has been attributed to the involvement of the Gi protein/protein kinase G pathway or to the activation of protein kinase C without an increase in intracellular Ca2+ concentration or in myofibrillar Ca2+ sensitivity. The chronic effect of ETs on the myocardium results in hypertrophy and prevention of apoptosis, two processes that are together responsible for the contradictory effect of ETs in heart failure.
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http://dx.doi.org/10.2459/01.JCM.0000242996.19077.baDOI Listing
September 2006

Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation.

Basic Res Cardiol 2006 Mar 6;101(2):180-9. Epub 2006 Feb 6.

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Ospedale S. Luigi, Regione Gonzole, 10043, Orbassano, TO, Italy.

Post-conditioning (Post-C) induced cardioprotection involves activation of guanylyl-cyclase. In the ischemic preconditioning scenario, the downstream targets of cGMP include mitochondrial ATP-sensitive K(+) (mK(ATP)) channels and protein kinase C (PKC), which involve reactive oxygen species (ROS) production. This study tests the hypothesis that mK(ATP), PKC and ROS are also involved in the Post-C protection. Isolated rat hearts underwent 30 min global ischemia (I) and 120 min reperfusion (R) with or without Post-C (i.e., 5 cycles of 10 s R/I immediately after the 30 min ischemia). In 6 groups (3 with and 3 without Post-C) either mK(ATP) channel blocker, 5- hydroxydecanoate (5-HD), or PKC inhibitor, chelerythrine (CHE) or ROS scavenger, N-acetyl-cysteine (NAC), were given during the entire reperfusion (120 min). In other 6 groups (3 with and 3 without Post-C), 5-HD, CHE or NAC were infused for 117 min only starting after 3 min of reperfusion not to interfere with the early effects of Post-C and/or reperfusion. In an additional group NAC was given during Post-C maneuvers (i.e., 3 min only). Myocardial damage was evaluated using nitro-blue tetrazolium staining and lactate dehydrogenase (LDH) release. Post-C attenuated myocardial infarct size (21 +/- 3% vs. 64 +/- 5% in control; p < 0.01). Such an effect was abolished by 5-HD or CHE given during either the 120 or 117 min of reperfusion as well as by NAC given during the 120 min or the initial 3 min of reperfusion. However, delayed NAC (i.e., 117 min infusion) did not alter the protective effect of Post- C (infarct size 32 +/- 5%; p < 0.01 vs. control, NS vs. Post-C). CHE, 5-HD or NAC given in the absence of Post-C did not alter the effects of I/R. Similar results were obtained in terms of LDH release. Our data show that Post-C induced protection involves an early redox-sensitive mechanism as well as a persistent activation of mK(ATP) and PKC, suggesting that the mK(ATP)/ROS/PKC pathway is involved in post-conditioning.
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http://dx.doi.org/10.1007/s00395-006-0584-5DOI Listing
March 2006

Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation.

Circ Res 2005 Oct 15;97(8):e73-83. Epub 2005 Sep 15.

Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

High-mobility group box 1 protein (HMGB1) is a chromatin protein that is released by inflammatory and necrotic cells. Extracellular HMGB1 signals tissue damage, stimulates the secretion of proinflammatory cytokines and chemokines, and modulates stem cell function. The present study examined exogenous HMGB1 effect on mouse left-ventricular function and myocyte regeneration after infarction. Myocardial infarction was induced in C57BL/6 mice by permanent coronary artery ligation. After 4 hours animals were reoperated and 200 ng of purified HMGB1 was administered in the peri-infarcted left ventricle. This intervention resulted in the formation of new myocytes within the infarcted portion of the wall. The regenerative process involved the proliferation and differentiation of endogenous cardiac c-kit+ progenitor cells. Circulating c-kit+ cells did not significantly contribute to HMGB1-mediated cardiac regeneration. Echocardiographic and hemodynamic parameters at 1, 2, and 4 weeks demonstrated a significant recovery of cardiac performance in HMGB1-treated mice. These effects were not observed in infarcted hearts treated either with the unrelated protein glutathione S-transferase or a truncated form of HMGB1. Thus, HMGB1 appears to be a potent inducer of myocardial regeneration following myocardial infarction.
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http://dx.doi.org/10.1161/01.RES.0000186276.06104.04DOI Listing
October 2005

Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival.

Circ Res 2005 Sep 1;97(7):663-73. Epub 2005 Sep 1.

Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.

Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 microm3 at 16 days after treatment and reached 5100 microm3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10,000 to 20,000 microm3. Moreover, there were 43+/-13 arterioles and 155+/-48 capillaries/mm2 myocardium at 16 days, and 31+/-6 arterioles and 390+/-56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function.
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http://dx.doi.org/10.1161/01.RES.0000183733.53101.11DOI Listing
September 2005

Post-conditioning reduces infarct size in the isolated rat heart: role of coronary flow and pressure and the nitric oxide/cGMP pathway.

Basic Res Cardiol 2006 Mar 19;101(2):168-79. Epub 2005 Aug 19.

Dipartimento di Scienze Cliniche e Biologiche dell'Università di Torino, Orbassano, TO, Italy.

We aimed to assess the role of the nitric oxide (NO)-cGMP pathway in cardioprotection by brief intermittent ischemias at the onset of reperfusion (i.e., post-conditioning (Post-con)). We also evaluated the role of coronary flow and pressure in Post-con. Rat isolated hearts perfused at constant- flow or -pressure underwent 30 min global ischemia and 120 min reperfusion. Post-con obtained with brief ischemias of different duration (modified, MPost-con) was compared with Post-con obtained with ischemias of identical duration (classical, C-Post-con) and with ischemic preconditioning (IP). Infarct size was evaluated using nitro-blue tetrazolium staining and lactate dehydrogenase (LDH) release. In the groups, NO synthase (NOS) or guanylyl-cyclase (GC) was inhibited with LNAME and ODQ, respectively. In the subgroups, the enzyme immunoassay technique was used to quantify cGMP release. In the constant-flow model, M-Post-con and C-Post-con were equally effective, but more effective than IP in reducing infarct size. The cardioprotection by M-Post-con was only blunted by the NOS-inhibitor, but was abolished by the GC-antagonist. Post-ischemic cGMP release was enhanced by MPost-con. In the constant-pressure model IP, M-Post-con and C-Post-con were equally effective in reducing infarct size. Post-con protocols were more effective in the constant-flow than in the constant-pressure model. In all groups, LDH release during reperfusion was proportional to infarct size. In conclusion, Post-con depends upon GC activation, which can be achieved by NOS-dependent and NOS-independent pathways. The benefits of M- and CPost-con are similar. However, protection by Post-con is greater in the constant-flow than in the constant-pressure model.
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http://dx.doi.org/10.1007/s00395-005-0543-6DOI Listing
March 2006

Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function.

Proc Natl Acad Sci U S A 2005 Mar 25;102(10):3766-71. Epub 2005 Feb 25.

Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.

The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair.
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http://dx.doi.org/10.1073/pnas.0405957102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC553298PMC
March 2005

F0F1 ATP synthase activity is differently modulated by coronary reactive hyperemia before and after ischemic preconditioning in the goat.

Am J Physiol Heart Circ Physiol 2004 Nov 24;287(5):H2192-200. Epub 2004 Jun 24.

Sezione di Fisiologia, Dipartimento di Neuroscienze and Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, 10100 Turin, Italy.

The amplitude of coronary reactive hyperemia (CRH), elicited by 15 s of ischemia, is reduced in hearts subjected to 5 min of ischemic preconditioning (IP). F0F1 ATP synthase activity and ATP concentration are also altered by IP. We hypothesized that F0F1 ATP synthase is differently modulated by the inhibitor protein IF(1) during CRH elicited before (CRHnp) and after (CRHprec) IP. Hemodynamic parameters were recorded in 10 anesthetized goats. Myocardial biopsies were obtained before IP (Cnp), during CRHnp, 4 and 6 min after the onset of CRHnp, after IP (Cprec), during CRHprec, and 4 min after CRHprec. F0F1 ATP synthase activity, ATP concentration, and ATP-to-ADP ratio (ATP/ADP) were determined. Compared with CRHnp, IP blunted CRHprec. F0F1 ATP synthase activity transiently increased during CRHnp, decreased 4 min after CRHnp, and returned to control 2 min later; it was lower after IP (Cprec) and did not change during and after CRHprec. All these changes in activity were modulated by IF1. During CRHnp, ATP concentration and ATP/ADP were reduced compared with Cnp and began to rise 6 min thereafter. During Cprec, both parameters were transiently reduced but increased during and after CRHprec. Hence, during CRHnp, F0F1 ATP synthase activity transiently increases and then decreases significantly. The short-lasting inhibition of the enzyme may explain why a few seconds of occlusion do not induce IP. After IP, F0F1 ATP synthase activity is blunted, and it is not affected by a subsequent 15 s of occlusion, which induces a blunted CRHprec. These results suggest that postischemic long-lasting inhibition of F0F1 ATP synthase activity may be a feature of the preconditioned heart. The increase in ATP concentration after preconditioning is in agreement with previous reports of reduced ATP hydrolysis by cytoplasmic ATPases.
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http://dx.doi.org/10.1152/ajpheart.00327.2004DOI Listing
November 2004

Coronary endothelial dysfunction after ischemia and reperfusion and its prevention by ischemic preconditioning.

Ital Heart J 2003 Jun;4(6):383-94

Department of Biological and Clinical Sciences, University of Turin, Turin, Italy.

In the coronary circulation, when reperfusion follows ischemia, endothelial dysfunction occurs. This is characterized by a reduced endothelial release of nitric oxide and by an increased release of reactive oxygen species and endothelin. The reduced availability of nitric oxide leads to the adhesion of neutrophils to the vascular endothelium, platelet aggregation and, with the contribution of endothelin, vasoconstriction, which are responsible for the "no-reflow" phenomenon. Neutrophil adhesion is followed by the release of the superoxide anion from neutrophils and endothelial cells. Preconditioning limits the endothelial damage by ischemia-reperfusion. A relevant role is attributed to the increased endothelial release of nitric oxide, while that of adenosine is controversial. Another effect of preconditioning on the coronary vasculature is the acceleration of vasodilation in reactive hyperemia after a brief coronary occlusion. The acceleration is prevented if myocardial protection is achieved by means of the activation of the mitochondrial adenosine triphosphate sensitive potassium channels by diazoxide and persists when ischemic preconditioning is induced after blockade of the same channels by 5-hydroxydecanoate.
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June 2003