Publications by authors named "Pagliaro Pasquale"

125 Publications

Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development.

Pharmacol Res 2021 Mar 26;168:105581. Epub 2021 Mar 26.

Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Arcavacata di Rende, CS, Italy.

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.
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http://dx.doi.org/10.1016/j.phrs.2021.105581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997688PMC
March 2021

Physical activity/inactivity and COVID-19.

Eur J Prev Cardiol 2020 May 19. Epub 2020 May 19.

Department of Clinical and Biological Science, University of Torino, Italy.

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http://dx.doi.org/10.1177/2047487320927597DOI Listing
May 2020

Extracellular Vesicles in Comorbidities Associated with Ischaemic Heart Disease: Focus on Sex, an Overlooked Factor.

J Clin Med 2021 Jan 17;10(2). Epub 2021 Jan 17.

Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Orbassano (TO), Italy.

Extracellular vesicles (EV) are emerging early markers of myocardial damage and key mediators of cardioprotection. Therefore, EV are becoming fascinating tools to prevent cardiovascular disease and feasible weapons to limit ischaemia/reperfusion injury. It is well known that metabolic syndrome negatively affects vascular and endothelial function, thus creating predisposition to ischemic diseases. Additionally, sex is known to significantly impact myocardial injury and cardioprotection. Therefore, actions able to reduce risk factors related to comorbidities in ischaemic diseases are required to prevent maladaptive ventricular remodelling, preserve cardiac function, and prevent the onset of heart failure. This implies that early diagnosis and personalised medicine, also related to sex differences, are mandatory for primary or secondary prevention. Here, we report the contribution of EV as biomarkers and/or therapeutic tools in comorbidities predisposing to cardiac ischaemic disease. Whenever possible, attention is dedicated to data linking EV to sex differences.
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http://dx.doi.org/10.3390/jcm10020327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830384PMC
January 2021

Anthracyclines and regional myocardial damage in breast cancer patients. A multicentre study from the Working Group on Drug Cardiotoxicity and Cardioprotection, Italian Society of Cardiology (SIC).

Eur Heart J Cardiovasc Imaging 2021 Mar;22(4):406-415

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Aims: In breast cancer (BC) patients treated with anthracyclines-based therapies, we aim at assessing whether adjuvant drugs impact cardiac function differently and whether their cardiotoxicity has a regional pattern.

Methods And Results: In a multicentre study, 146 BC patients (56 ± 11 years) were prospectively enrolled and divided into three groups according to the received treatments: AC/EC-Group (doxorubicin or epirubicin + cyclophosphamide), AC/EC/Tax-Group (AC/EC + taxanes), FEC/Tax-Group (fluorouracil + EC + taxanes). Fifty-six patients of the total cohort also received trastuzumab. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were calculated before starting chemotherapy (T0), at 3 months (T3), at 6 (T6), and 12 months (T12). A ≥10% drop of EF, while remaining within the normal range, was reached at T6 in 25.3% of patients from the whole cohort with an early decrease only in FEC/Tax-Group (P = 0.04). A ≥15% GLS reduction was observed in many more (61.6%) patients. GLS decreased early both in the whole population (P < 0.001) and in the subgroups. The FEC-Tax Group showed the worst GLS at T6. Trastuzumab further worsened GLS at T12 (P = 0.031). A significant reduction of GLS was observed in all LV segments and was more relevant in the anterior septum and apex.

Conclusions: The decrease of GLS is more precocious and pronounced in BC patients who received FEC + taxanes. Cardiac function further worsens after 6 months of adjuvant trastuzumab. All LV segments are damaged, with the anterior septum and the apex showing the greatest impairments.
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http://dx.doi.org/10.1093/ehjci/jeaa339DOI Listing
March 2021

The Inflammatory Cytokine IL-3 Hampers Cardioprotection Mediated by Endothelial Cell-Derived Extracellular Vesicles Possibly via Their Protein Cargo.

Cells 2020 Dec 23;10(1). Epub 2020 Dec 23.

Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy.

The biological relevance of extracellular vesicles (EV) released in an ischemia/reperfusion setting is still unclear. We hypothesized that the inflammatory microenvironment prevents cardioprotection mediated by endothelial cell (EC)-derived extracellular vesicles. The effects of naïve EC-derived EV (eEV) or eEV released in response to interleukin-3 (IL-3) (eEV-IL-3) were evaluated in cardiomyoblasts (H9c2) and rat hearts. In transwell assay, eEV protected the H9c2 exposed to hypoxia/reoxygenation (H/R) more efficiently than eEV-IL-3. Conversely, only eEV directly protected H9c2 cells to H/R-induced damage. Consistent with this latter observation, eEV, but not eEV-IL-3, exerted beneficial effects in the whole heart. Protein profiles of eEV and eEV-IL-3, established using label-free mass spectrometry, demonstrated that IL-3 drives changes in eEV-IL-3 protein cargo. Gene ontology analysis revealed that both eEV and eEV-IL-3 were equipped with full cardioprotective machinery, including the . eEV-IL-3 were also enriched in the endothelial-nitric oxide-synthase (eNOS)-antagonist caveolin-1 and proteins related to the inflammatory response. In vitro and ex vivo experiments demonstrated that a functional Mitogen-Activated Protein Kinase Kinase (MEK1/2)/eNOS/guanylyl-cyclase (GC) pathway is required for eEV-mediated cardioprotection. Consistently, eEV were found enriched in MEK1/2 and able to induce the expression of B-cell-lymphoma-2 (Bcl-2) and the phosphorylation of eNOS in vitro. We conclude that an inflammatory microenvironment containing IL-3 changes the eEV cargo and impairs eEV cardioprotective action.
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http://dx.doi.org/10.3390/cells10010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822476PMC
December 2020

Extracellular vesicles and cardiovascular system: Biomarkers and Cardioprotective Effectors.

Vascul Pharmacol 2020 12 28;135:106790. Epub 2020 Aug 28.

Department of Clinical and Biological Sciences, University of Turin. Regione Gonzole 10, 10043, Orbassano (TO), Italy. Electronic address:

In the last few decades extracellular vesicles (EVs), which include exosomes and microvesicles, have attracted significant interest in cardiovascular pathophysiology due to their intrinsic properties. Indeed, EVs by transferring their cargo, which contains miRNA, DNA, proteins and lipids, were found effective in preventive and regenerative medicine and in protecting the heart against an array of pathological conditions, including myocardial infarction and arrhythmias. EVs can attenuate cellular senescence, inflammation and myocardial injury. Cardiovascular structures may be targeted by circulating EVs derived by extra-cardiac cells and platelets, as well by EVs locally released from all major cardiovascular cell types, including endothelial cells, cardiomyocytes, macrophages and fibroblasts. Yet, EVs of cardiovascular origin can be also transferred to distant tissues by circulation. Therefore, EVs have been proposed not only as promising diagnostic tools (early disease biomarkers), but also as therapeutics. This review focuses on the protective effects exerted by EVs, released by different cell types in the cardiovascular system. Physical exercise is considered as a natural mechanism of EV production involved in preventive medicine. Particular attention will be devoted to describe the impact of EVs in cardioprotection after ischemia/reperfusion injury.
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http://dx.doi.org/10.1016/j.vph.2020.106790DOI Listing
December 2020

Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades.

Oxid Med Cell Longev 2020 3;2020:9219825. Epub 2020 Aug 3.

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

Inhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protection induced by the P2Y12 receptor antagonist Ticagrelor. Ticagrelor (150 mg/kg) was orally administered to rats for three consecutive days. Then, isolated hearts underwent an ischemia/reperfusion (30 min ischemia/60 min reperfusion; IR) protocol. The selective NLRP3 inflammasome inhibitor INF (50 M) was infused before the IR protocol to the hearts from untreated animals or pretreated with Ticagrelor. In parallel experiments, the hearts isolated from untreated animals were perfused with Ticagrelor (3.70 M) before ischemia and subjected to IR. The hearts of animals pretreated with Ticagrelor showed a significantly reduced infarct size (IS, 49 ± 3% of area at risk, AAR) when compared to control IR group (69 ± 2% of AAR). Similarly, administration of INF before the IR injury resulted in significant IS reduction (38 ± 3% of AAR). Myocardial IR induced the NLRP3 inflammasome complex formation, which was attenuated by either INF pretreatment , or by repeated oral treatment with Ticagrelor. The beneficial effects induced by either treatment were associated with the protective Reperfusion Injury Salvage Kinase (RISK) pathway activation and redox defence upregulation. In contrast, no protective effects nor NLRP3/RISK modulation were recorded when Ticagrelor was administered before ischemia in isolated heart, indicating that Ticagrelor direct target is not in the myocardium. Our results confirm that Ticagrelor conditioning effects are likely mediated through platelets, but are not additives to the ones achieved by directly inhibiting NLRP3.
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http://dx.doi.org/10.1155/2020/9219825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424511PMC
August 2020

Sex-related differences in COVID-19 lethality.

Br J Pharmacol 2020 10 5;177(19):4375-4385. Epub 2020 Aug 5.

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

Many countries have been affected by the worldwide outbreak of COVID-19. Among Western countries, Italy has been particularly hit at the beginning of the pandemic, immediately after China. In Italy and elsewhere, women seem to be less affected than men by severe/fatal COVID-19 infection, regardless of their age. Although women and men are affected differently by this infection, very few studies consider different therapeutic approaches for the two sexes. Understanding the mechanisms underlying these differences may help to find appropriate and sex specific therapies. Here, we consider that other mechanisms are involved to explain this difference, in addition to the protection attributable to oestrogens. Several X-linked genes (such as ACE2) and Y-linked genes (SRY and SOX9) may explain sex differences. Cardiovascular comorbidities are among the major enhancers of virus lethality. In addition, the number of sex-independent, non-genetic factors that can change susceptibility and mortality is enormous, and many other factors should be considered, including gender and cultural habits in different countries.
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http://dx.doi.org/10.1111/bph.15207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405496PMC
October 2020

Is macrophages heterogeneity important in determining COVID-19 lethality?

Med Hypotheses 2020 Oct 3;143:110073. Epub 2020 Jul 3.

Dpt Clinical and Biological Sciences, University of Torino, Italy. Electronic address:

COVID-19 (coronavirus disease 2019) pandemic due to infection with SARS-CoV-2 has led to the death of thousands of adults worldwide. It is now clear that the hyper-inflammatory response triggered by SARS-CoV-2 plays a major role in disease severity and lethality of the infection. Macrophages are innate immune cells that sense and respond to infections by producing a plethora of inflammatory molecules and by interacting with other inflammatory cells. Therefore, macrophages may be diriment on eliminating pathogens and promoting organ repair. However, macrophages can be a major player of the so called cytokine storm and may be damaging to the tissues. It is believed that macrophage activation syndrome is induced by SARS-CoV to be lethal. Surprisingly and fortunately few children die from COVID-19. For instance, in Italy, out of more than 30.000 deaths for COVID-19, three are children. Therefore, we must wonder why? Are macrophages different in children compared to adults? In my opinion they are different. It has been demonstrated that macrophages populate the lung in three "developmental waves", and it has been suggested that similar waves may be observed in other important organs, such as the heart and kidney. It is most likely that macrophages heterogeneity is involved in determining the severity. There are no doubts that macrophages are important in determining life or death in these patients. Comparing macrophages of children with those of adults with different degrees of disease severity is, therefore, mandatory.
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http://dx.doi.org/10.1016/j.mehy.2020.110073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332450PMC
October 2020

ACE/ACE2 Ratio: A Key Also in 2019 Coronavirus Disease (Covid-19)?

Front Med (Lausanne) 2020 18;7:335. Epub 2020 Jun 18.

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

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http://dx.doi.org/10.3389/fmed.2020.00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314898PMC
June 2020

The COVID-19 Pandemic: A Challenge for the Cardiovascular Health.

Curr Cardiol Rev 2020 ;16(2):vi-xi

Department of Clinical and Biological Science, University of Torino, Torino, Italy.

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http://dx.doi.org/10.2174/1573403X1602200519115447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460706PMC
January 2020

Physical activity/inactivity and COVID-19.

Eur J Prev Cardiol 2020 May 18:2047487320927597. Epub 2020 May 18.

Department of Clinical and Biological Science, University of Torino, Italy.

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http://dx.doi.org/10.1177/2047487320927597DOI Listing
May 2020

Diabetic Cardiomyopathy and Ischemic Heart Disease: Prevention and Therapy by Exercise and Conditioning.

Int J Mol Sci 2020 Apr 21;21(8). Epub 2020 Apr 21.

Department of Clinical and Biological Science, University of Torino, 10043 Obassano (TO), Italy.

Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. In addition, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.
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http://dx.doi.org/10.3390/ijms21082896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215312PMC
April 2020

Back and forth from basic science to clinical translation.

Minerva Anestesiol 2020 Aug 11;86(8):890-891. Epub 2020 Mar 11.

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

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http://dx.doi.org/10.23736/S0375-9393.20.14555-3DOI Listing
August 2020

Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury.

J Cell Mol Med 2020 04 10;24(7):3795-3806. Epub 2020 Mar 10.

IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain.

Acute myocardial infarction causes lethal injury to cardiomyocytes during both ischaemia and reperfusion (IR). It is important to define the precise mechanisms by which they die in order to develop strategies to protect the heart from IR injury. Necrosis is known to play a major role in myocardial IR injury. There is also evidence for significant myocardial death by other pathways such as apoptosis, although this has been challenged. Mitochondria play a central role in both of these pathways of cell death, as either a causal mechanism is the case of mitochondrial permeability transition leading to necrosis, or as part of the signalling pathway in mitochondrial cytochrome c release and apoptosis. Autophagy may impact this process by removing dysfunctional proteins or even entire mitochondria through a process called mitophagy. More recently, roles for other programmed mechanisms of cell death such as necroptosis and pyroptosis have been described, and inhibitors of these pathways have been shown to be cardioprotective. In this review, we discuss both mitochondrial and mitochondrial-independent pathways of the major modes of cell death, their role in IR injury and their potential to be targeted as part of a cardioprotective strategy. This article is part of a special Issue entitled 'Mitochondria as targets of acute cardioprotection' and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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http://dx.doi.org/10.1111/jcmm.15127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171390PMC
April 2020

Effect of hyperglycaemia and diabetes on acute myocardial ischaemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols.

Br J Pharmacol 2020 12 9;177(23):5312-5335. Epub 2020 Mar 9.

The Hatter Cardiovascular Institute, University College London, London, UK.

Diabetic patients are at increased risk of developing coronary artery disease and experience worse clinical outcomes following acute myocardial infarction. Novel therapeutic strategies are required to protect the myocardium against the effects of acute ischaemia-reperfusion injury (IRI). These include one or more brief cycles of non-lethal ischaemia and reperfusion prior to the ischaemic event (ischaemic preconditioning [IPC]) or at the onset of reperfusion (ischaemic postconditioning [IPost]) either to the heart or to extracardiac organs (remote ischaemic conditioning [RIC]). Studies suggest that the diabetic heart is resistant to cardioprotective strategies, although clinical evidence is lacking. We overview the available animal models of diabetes, investigating acute myocardial IRI and cardioprotection, experiments investigating the effects of hyperglycaemia on susceptibility to acute myocardial IRI, the response of the diabetic heart to cardioprotective strategies e.g. IPC, IPost and RIC. Finally we highlight the effects of anti-hyperglycaemic agents on susceptibility to acute myocardial IRI and cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.
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http://dx.doi.org/10.1111/bph.14993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680002PMC
December 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

Obesity and Cardioprotection.

Curr Med Chem 2020 ;27(2):230-239

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

The incidence of obesity and diabetes is increasing rapidly worldwide. Obesity and metabolic syndrome are strictly linked and represent the basis of different cardiovascular risk factors, including hypertension and inflammatory processes predisposing to ischemic heart disease, which represent the most common causes of heart failure. Recent advances in the understanding of ischemia/reperfusion mechanisms of injury and mechanisms of cardioprotection are briefly considered. Resistance to cardioprotection may be correlated with the severity of obesity. The observation that heart failure obese patients have a better clinical condition than lean heart failure patients is known as "obesity paradox". It seems that obese patients with heart failure are younger, making age the most important confounder in some studies. Critical issues are represented by the "obesity paradox" and heart failure exacerbation by inflammation. For heart failure exacerbation by inflammation, an important role is played by NLRP3 inflammasome, which is emerging as a possible target for heart failure condition. These critical issues in the field of obesity and cardiovascular diseases need more studies to ascertain which metabolic alterations are crucial for alleged beneficial and deleterious effects of obesity.
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http://dx.doi.org/10.2174/0929867326666190325094453DOI Listing
February 2020

Circulating blood cells and extracellular vesicles in acute cardioprotection.

Cardiovasc Res 2019 06;115(7):1156-1166

Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest 1089, Hungary.

During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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http://dx.doi.org/10.1093/cvr/cvy314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529916PMC
June 2019

Innate immunity as a target for acute cardioprotection.

Cardiovasc Res 2019 06;115(7):1131-1142

The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, UK.

Acute obstruction of a coronary artery causes myocardial ischaemia and if prolonged, may result in an ST-segment elevation myocardial infarction (STEMI). First-line treatment involves rapid reperfusion. However, a highly dynamic and co-ordinated inflammatory response is rapidly mounted to repair and remove the injured cells which, paradoxically, can further exacerbate myocardial injury. Furthermore, although cardiac remodelling may initially preserve some function to the heart, it can lead over time to adverse remodelling and eventually heart failure. Since the size of the infarct corresponds to the subsequent risk of developing heart failure, it is important to find ways to limit initial infarct development. In this review, we focus on the role of the innate immune system in the acute response to ischaemia-reperfusion (IR) and specifically its contribution to cell death and myocardial infarction. Numerous danger-associated molecular patterns are released from dying cells in the myocardium, which can stimulate pattern recognition receptors including toll like receptors and NOD-like receptors (NLRs) in resident cardiac and immune cells. Activation of the NLRP3 inflammasome, caspase 1, and pyroptosis may ensue, particularly when the myocardium has been previously aggravated by the presence of comorbidities. Evidence will be discussed that suggests agents targeting innate immunity may be a promising means of protecting the hearts of STEMI patients against acute IR injury. However, the dosing and timing of such agents should be carefully determined because innate immunity pathways may also be involved in cardioprotection. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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http://dx.doi.org/10.1093/cvr/cvy304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529915PMC
June 2019

Hemodynamic abnormalities during muscle metaboreflex activation in patients with type 2 diabetes mellitus.

J Appl Physiol (1985) 2019 02 13;126(2):444-453. Epub 2018 Dec 13.

Sports Physiology Laboratory, Department of Medical Sciences and Public Health, University of Cagliari , Cagliari , Italy.

Metaboreflex is a reflex triggered during exercise or postexercise muscle ischemia (PEMI) by metaboreceptor stimulation. Typical features of metaboreflex are increased cardiac output (CO) and blood pressure. Patients suffering from metabolic syndrome display hemodynamic abnormalities, with an exaggerated systemic vascular resistance (SVR) and reduced CO response during PEMI-induced metaboreflex. Whether patients with type 2 diabetes mellitus (DM2) have similar hemodynamic abnormalities is unknown. Here we contrast the hemodynamic response to PEMI in 14 patients suffering from DM2 (age 62.7 ± 8.3 yr) and in 15 age-matched controls (CTLs). All participants underwent a control exercise recovery reference test and a PEMI test to obtain the metaboreflex response. Central hemodynamics were evaluated by unbiased operator-independent impedance cardiography. Although the blood pressure response to PEMI was not significantly different between the groups, we found that the SVR and CO responses were reversed in patients with DM2 as compared with the CTLs (SVR: 392.5 ± 549.6 and -14.8 ± 258.9 dyn·s·cm; CO: -0.25 ± 0.63 and 0.46 ± 0.50 l/m, respectively, in DM2 and in CTL groups, respectively; P < 0.05 for both). Of note, stroke volume (SV) increased during PEMI in the CTL group only. Failure to increase SV and CO was the consequence of reduced venous return, impaired cardiac performance, and augmented afterload in patients with DM2. We conclude that patients with DM2 have an exaggerated vasoconstriction in response to metaboreflex activation not accompanied by a concomitant increase in heart performance. Therefore, in these patients, blood pressure response to the metaboreflex relies more on SVR increases rather than on increases in SV and CO. NEW & NOTEWORTHY The main new finding of the present investigation is that subjects with type 2 diabetes mellitus have an exaggerated vasoconstriction in response to metaboreflex activation. In these patients, blood pressure response to the metaboreflex relies more on systemic vascular resistance than on cardiac output increments.
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http://dx.doi.org/10.1152/japplphysiol.00794.2018DOI Listing
February 2019

Editorial: Redox and Nitrosative Signaling in Cardiovascular System: From Physiological Response to Disease.

Front Physiol 2018 2;9:1538. Epub 2018 Nov 2.

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

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http://dx.doi.org/10.3389/fphys.2018.01538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224784PMC
November 2018

Role of NLRP-3 Inflammasome in Hypertension: A Potential Therapeutic Target.

Curr Pharm Biotechnol 2018 ;19(9):708-714

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

Background: Hypertension is a multifactorial and chronic cardiovascular condition whose complications are responsible for worldwide morbidity and mortality. An increasing body of experimental data, recognize low-grade inflammation as a basic process in hypertension onset and development since there is a strong contribution of both the innate and the adaptive immune system according to the so-called Danger-Model. In this contest, NLRP3 inflammasome represents a key signaling platform as demonstrated by its implication in several hypertension-associated conditions, such as vascular smooth muscle remodeling and proliferation. This intracellular receptor is activated by Pathogenassociated molecular pattern molecules/damage-associated molecular pattern molecules signals and its mechanism of action converges on the final production of caspase-1 and, consequently, of the proinflammatory cytokines IL-1β and IL-18.

Objective: The aim of the present work was to point out the role of the NLRP3 inflammasome complex in the hypertensive pathology and to describe it as a new potential therapeutic target.

Method: A systematic review of the literature data related to NLRP3 and hypertension correlation has been performed.

Results: Numerous and well-designed experiments demonstrate that the inflammasome plays a crucial role in essential and high-salt dependent hypertension, as well as in preeclampsia, in pulmonary hypertension, and in its related secondary disorders; its mechanism includes both a central nervous and a peripheral modulation of the inflammatory pathways. To date, research is trying to design inflammasome antagonists or equivalent inhibition strategies.

Conclusion: The inflammasome represents a leading promoter of hypertensive inflammation opening new perspective in the field of the clinical approach in this pathology.
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http://dx.doi.org/10.2174/1389201019666180808162011DOI Listing
February 2019

Cardioprotective Properties of Human Platelets Are Lost in Uncontrolled Diabetes Mellitus: A Study in Isolated Rat Hearts.

Front Physiol 2018 10;9:875. Epub 2018 Jul 10.

Department of Clinical and Biological Sciences, AOU San Luigi, University of Turin, Turin, Italy.

Platelets affect myocardial damage from ischemia/reperfusion. Redox-dependent sphingosine-1-phosphate production and release are altered in diabetic platelets. Sphingosine-1-phosphate is a double-edged sword for ischemia/reperfusion injury. Therefore, we aimed to verify whether: (1) human healthy- or diabetic-platelets are cardioprotective, (2) sphingosine-1-phosphate receptors and downstream kinases play a role in platelet-induced cardioprotection, and (3) a correlation between platelet redox status and myocardial ischemia/reperfusion injury exists. Isolated rat hearts were subjected to 30-min ischemia and 1-h reperfusion. Infarct size was studied in hearts pretreated with healthy- or diabetic-platelets. Healthy-platelets were co-infused with sphingosine-1-phosphate receptor blocker, ERK-1/2 inhibitor, PI3K antagonist or PKC inhibitor to ascertain the cardioprotective mechanisms. In platelets we assessed (i) aggregation response to ADP, collagen, and arachidonic-acid, (ii) cyclooxygenase-1 levels, and (iii) AKT and ERK-phosphorylation. Platelet sphingosine-1-phosphate production and platelet levels of reactive oxygen species (ROS) were quantified and correlated to infarct size. Infarct size was reduced by about 22% in healthy-platelets pretreated hearts only. This cardioprotective effect was abrogated by either sphingosine-1-phosphate receptors or ERK/PI3K/PKC pathway blockade. Cyclooxygenase-1 levels and aggregation indices were higher in diabetic-platelets than healthy-platelets. Diabetic-platelets released less sphingosine-1-phosphate than healthy-platelets when mechanical or chemically stimulated . Yet, ROS levels were higher in diabetic-platelets and correlated with infarct size. Cardioprotective effects of healthy-platelet depend on the platelet's capacity to activate cardiac sphingosine-1-phosphate receptors and ERK/PI3K/PKC pathways. However, diabetic-platelets release less S1P and lose cardioprotective effects. Platelet ROS levels correlate with infarct size. Whether these redox alterations are responsible for sphingosine-1-phosphate dysfunction in diabetic-platelets remains to be ascertained.
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http://dx.doi.org/10.3389/fphys.2018.00875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048273PMC
July 2018

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

Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts.

Front Physiol 2018 15;9:521. Epub 2018 May 15.

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

G protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER interaction is involved in the limitation of infarct size, and improvement of post-ischemic contractile function in female spontaneous hypertensive rat (SHR) hearts. In this model, we also studied Notch signaling and key components of survival pathway, namely PI3K-Akt, nitric oxide synthase (NOS) and mitochondrial K-ATP (MitoKATP) channels. Rat hearts isolated from female SHR underwent 30 min of global, normothermic ischemia and 120 min of reperfusion. G1 (10 nM) alone or specific inhibitors of GPER, PI3K/NOS and MitoKATP channels co-infused with G1, just before I/R, were studied. The involvement of Notch1 was studied by Western blotting. Infarct size and left ventricular pressure were measured. To confirm endothelial-independent G1-induced protection by Notch signaling, H9c2 cells were studied with specific inhibitor, -[-(3,5 difluorophenacetyl)-L-alanyl]--phenylglycine -butyl ester (DAPT, 5 μM), of this signaling. Using DAPT, we confirmed the involvement of G1/Notch signaling in limiting infarct size in heart of normotensive animals. In the hypertensive model, G1-induced reduction in infarct size and improvement of cardiac function were prevented by the inhibition of GPER, PI3K/NOS, and MitoKATP channels. The involvement of Notch was confirmed by western blot in the hypertensive model and by the specific inhibitor in the normotensive model and cardiac cell line. Our results suggest that GPERs play a pivotal role in mediating preconditioning cardioprotection in normotensive and hypertensive conditions. The G1-induced protection involves Notch1 and is able to activate the survival pathway in the presence of comorbidity. Several pathological conditions, including hypertension, reduce the efficacy of ischemic conditioning strategies. However, G1-induced protection can result in significant reduction of I/R injury also female in hypertensive animals. Further studies may ascertain the clinical translation of the present results.
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http://dx.doi.org/10.3389/fphys.2018.00521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962667PMC
May 2018

Editorial: Alteration of Redox Equilibrium, Inflammation and Progression of Disease.

Curr Med Chem 2018;25(11):1272-1274

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

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http://dx.doi.org/10.2174/092986732511180417115122DOI Listing
June 2018

Mitochondria in Cardiac Postconditioning.

Front Physiol 2018 26;9:287. Epub 2018 Mar 26.

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

Mitochondria play a pivotal role in cardioprotection. Here we report some fundamental studies which considered the role of mitochondrial components (connexin 43, mitochondrial KATP channels and mitochondrial permeability transition pore) in postconditioning cardioprotection. We briefly discuss the role of mitochondria, reactive oxygen species and gaseous molecules in postconditioning. Also the effects of anesthetics-used as cardioprotective substances-is briefly considered in the context of postconditioning. The role of mitochondrial postconditioning signaling in determining the limitation of cell death is underpinned. Issues in clinical translation are briefly considered. The aim of the present mini-review is to discuss in a historical perspective the role of main mitochondria mechanisms in cardiac postconditioning.
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http://dx.doi.org/10.3389/fphys.2018.00287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879113PMC
March 2018

Redox Aspects of Chaperones in Cardiac Function.

Front Physiol 2018 16;9:216. Epub 2018 Mar 16.

Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.

Molecular chaperones are stress proteins that allow the correct folding or unfolding as well as the assembly or disassembly of macromolecular cellular components. Changes in expression and post-translational modifications of chaperones have been linked to a number of age- and stress-related diseases including cancer, neurodegeneration, and cardiovascular diseases. Redox sensible post-translational modifications, such as S-nitrosylation, glutathionylation and phosphorylation of chaperone proteins have been reported. Redox-dependent regulation of chaperones is likely to be a phenomenon involved in metabolic processes and may represent an adaptive response to several stress conditions, especially within mitochondria, where it impacts cellular bioenergetics. These post-translational modifications might underlie the mechanisms leading to cardioprotection by conditioning maneuvers as well as to ischemia/reperfusion injury. In this review, we discuss this topic and focus on two important aspects of redox-regulated chaperones, namely redox regulation of mitochondrial chaperone function and cardiac protection against ischemia/reperfusion injury.
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http://dx.doi.org/10.3389/fphys.2018.00216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864891PMC
March 2018