Publications by authors named "Chowdhury S Abdullah"

14 Publications

  • Page 1 of 1

Sigmar1's Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology.

Front Physiol 2021 7;12:705575. Epub 2021 Jul 7.

Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States.

The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1's subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1's molecular, cellular, pathophysiological, and biological functions.
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http://dx.doi.org/10.3389/fphys.2021.705575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293995PMC
July 2021

Dysfunctional Mitochondrial Dynamic and Oxidative Phosphorylation Precedes Cardiac Dysfunction in R120G-αB-Crystallin-Induced Desmin-Related Cardiomyopathy.

J Am Heart Assoc 2020 12 19;9(23):e017195. Epub 2020 Nov 19.

Department of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LA.

Background The mutated α-B-Crystallin (CryAB) mouse model of desmin-related myopathy (DRM) shows an age-dependent onset of pathologic cardiac remodeling and progression of heart failure. CryAB expression in cardiomyocytes affects the mitochondrial spatial organization within the myofibrils, but the molecular perturbation within the mitochondria in the relation of the overall course of the proteotoxic disease remains unclear. Methods and Results CryAB mice show an accumulation of electron-dense aggregates and myofibrillar degeneration associated with the development of cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause cardiac contractility impairment, the molecular mechanism of cardiomyocyte death remains elusive. Here, we explore early pathological processes within the mitochondria contributing to the contractile dysfunction and determine the pathogenic basis for the heart failure observed in the CryAB mice. In the present study, we report that the CryAB mice transgenic hearts undergo altered mitochondrial dynamics associated with increased level of dynamin-related protein 1 and decreased level of optic atrophy type 1 as well as mitofusin 1 over the disease process. In association with these changes, an altered level of the components of mitochondrial oxidative phosphorylation and pyruvate dehydrogenase complex regulatory proteins occurs before the manifestation of pathologic adverse remodeling in the CryAB hearts. Mitochondria isolated from CryAB transgenic hearts without visible pathology show decreased electron transport chain complex activities and mitochondrial respiration. Taken together, we demonstrated the involvement of mitochondria in the pathologic remodeling and progression of DRM-associated cellular dysfunction. Conclusions Mitochondrial dysfunction in the form of altered mitochondrial dynamics, oxidative phosphorylation and pyruvate dehydrogenase complex proteins level, abnormal electron transport chain complex activities, and mitochondrial respiration are evident on the CryAB hearts before the onset of detectable pathologies and development of cardiac contractile dysfunction.
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http://dx.doi.org/10.1161/JAHA.120.017195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763772PMC
December 2020

Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function.

Commun Biol 2020 11 17;3(1):682. Epub 2020 Nov 17.

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA.

Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of "binge and crash" methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of "binge and crash" methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to "binge and crash" methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.
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http://dx.doi.org/10.1038/s42003-020-01408-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673131PMC
November 2020

Chemical Architecture of Block Copolymers Differentially Abrogate Cardiotoxicity and Maintain the Anticancer Efficacy of Doxorubicin.

Mol Pharm 2020 12 5;17(12):4676-4690. Epub 2020 Nov 5.

Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, North Dakota 58108, United States.

The molecular architecture of pH-responsive amphiphilic block copolymers, their self-assembly behavior to form nanoparticles (NPs), and doxorubicin (DOX)-loading technique govern the extent of DOX-induced cardiotoxicity. We observed that the choice of pH-sensitive tertiary amines, surface charge, and DOX-loading techniques within the self-assembled NPs strongly influence the release and stimulation of DOX-induced cardiotoxicity in primary cardiomyocytes. However, covalent conjugation of DOX to a pH-sensitive nanocarrier through a "conditionally unstable amide" linkage (PCPY-cDOX; PC = polycarbonate and PY = 2-pyrrolidine-1-yl-ethyl-amine) significantly reduced the cardiotoxicity of DOX in cardiomyocytes as compared to noncovalently encapsulated DOX NPs (PCPY-eDOX). When these formulations were tested for drug release in serum-containing media, the PCPY-cDOX systems showed prolonged control over drug release (for ∼72 h) at acidic pH compared to DOX-encapsulated nanocarriers, as expected. We found that DOX-encapsulated nanoformulations triggered cardiotoxicity in primary cardiomyocytes more acutely, while conjugated systems such as PCPY-cDOX prevented cardiotoxicity by disabling the nuclear entry of the drug. Using 2D and 3D (spheroid) cultures of an ER + breast cancer cell line (MCF-7) and a triple-negative breast cancer cell line (MDA-MB-231), we unravel that, similar to encapsulated systems (PCPY-eDOX-type) as reported earlier, the PCPY-cDOX system suppresses cellular proliferation in both cell lines and enhances trafficking through 3D spheroids of MDA-MB-231 cells. Collectively, our studies indicate that PCPY-cDOX is less cardiotoxic as compared to noncovalently encapsulated variants without compromising the chemotherapeutic properties of the drug. Thus, our studies suggest that the appropriate selection of the nanocarrier for DOX delivery may prove fruitful in shifting the balance between low cardiotoxicity and triggering the chemotherapeutic potency of DOX.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00963DOI Listing
December 2020

Molecular Perspectives of Mitochondrial Adaptations and Their Role in Cardiac Proteostasis.

Front Physiol 2020 27;11:1054. Epub 2020 Aug 27.

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, United States.

Mitochondria are the key to properly functioning energy generation in the metabolically demanding cardiomyocytes and thus essential to healthy heart contractility on a beat-to-beat basis. Mitochondria being the central organelle for cellular metabolism and signaling in the heart, its dysfunction leads to cardiovascular disease. The healthy mitochondrial functioning critical to maintaining cardiomyocyte viability and contractility is accomplished by adaptive changes in the dynamics, biogenesis, and degradation of the mitochondria to ensure cellular proteostasis. Recent compelling evidence suggests that the classical protein quality control system in cardiomyocytes is also under constant mitochondrial control, either directly or indirectly. Impairment of cytosolic protein quality control may affect the position of the mitochondria in relation to other organelles, as well as mitochondrial morphology and function, and could also activate mitochondrial proteostasis. Despite a growing interest in the mitochondrial quality control system, very little information is available about the molecular function of mitochondria in cardiac proteostasis. In this review, we bring together current understanding of the adaptations and role of the mitochondria in cardiac proteostasis and describe the adaptive/maladaptive changes observed in the mitochondrial network required to maintain proteomic integrity. We also highlight the key mitochondrial signaling pathways activated in response to proteotoxic stress as a cellular mechanism to protect the heart from proteotoxicity. A deeper understanding of the molecular mechanisms of mitochondrial adaptations and their role in cardiac proteostasis will help to develop future therapeutics to protect the heart from cardiovascular diseases.
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http://dx.doi.org/10.3389/fphys.2020.01054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481364PMC
August 2020

Pleiotropic effects of mdivi-1 in altering mitochondrial dynamics, respiration, and autophagy in cardiomyocytes.

Redox Biol 2020 09 26;36:101660. Epub 2020 Jul 26.

Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, 71103, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, 71103, USA. Electronic address:

Mitochondria are highly dynamic organelles that constantly undergo fission and fusion events to adapt to changes in the cellular environment. Aberrant mitochondrial fission has been associated with several types of cardiovascular dysfunction; inhibition of pathologically aberrant mitochondrial fission has been shown to be cardioprotective. Pathological fission is mediated by the excessive activation of GTPase dynamin-related protein 1 (Drp1), making it an attractive therapeutic target in numerous cardiovascular diseases. Mitochondrial division inhibitor (mdivi-1) is widely used small molecule reported to inhibit Drp1-dependent fission, elongate mitochondria, and mitigate injury. The purpose of our study was to understand the pleiotropic effects of mdivi-1 on mitochondrial dynamics, mitochondrial respiration, electron transport activities, and macro-autophagy. In this study, we found that mdivi-1 treatment decreased Drp1 expression, proteolytically cleaved L-OPA1, and altered the expression of OXPHOS complex proteins, resulting in increased superoxide production. The altered expression of OXPHOS complex proteins may be directly associated with decreased Drp1 expression, as Drp1 siRNA knockdown in cardiomyocytes showed similar effects. Results from an autophagy flux assay showed that mdivi-1 induced impaired autophagy flux that could be restored by Atg7 overexpression, suggesting that mdivi-1 mediated inhibition of macro-autophagy in cardiomyocytes. Treatment with mdivi-1 resulted in increased expression of p62, which is required for Atg7 overexpression-induced rescue of mdivi-1-mediated impaired autophagy flux. In addition, mdivi-1-dependent proteolytic processing of L-OPA1 was associated with increased mitochondrial superoxide production and altered expression of mitochondrial serine/proteases. Overall, the novel pleiotropic effect of mdivi-1 in cardiomyocytes included proteolytically cleaved L-OPA1, altered expression of OXPHOS complex proteins, and increased superoxide production, which together resulted in defects in mitochondrial respiration and inhibition of macro-autophagy.
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http://dx.doi.org/10.1016/j.redox.2020.101660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396909PMC
September 2020

Neurogranin regulates eNOS function and endothelial activation.

Redox Biol 2020 07 5;34:101487. Epub 2020 Mar 5.

Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA. Electronic address:

Endothelial nitric oxide (NO) is a critical mediator of vascular function and vascular remodeling. NO is produced by endothelial nitric oxide synthase (eNOS), which is activated by calcium (Ca)-dependent and Ca-independent pathways. Here, we report that neurogranin (Ng), which regulates Ca-calmodulin (CaM) signaling in the brain, is uniquely expressed in endothelial cells (EC) of human and mouse vasculature, and is also required for eNOS regulation. To test the role of Ng in eNOS activation, Ng knockdown in human aortic endothelial cells (HAEC) was performed using Ng SiRNA along with Ng knockout (Ng ) in mice. Depletion of Ng expression decreased eNOS activity in HAEC and NO production in mice. We show that Ng expression was decreased by short-term laminar flow and long-them oscillating flow shear stress, and that Ng siRNA with shear stress decreased eNOS expression as well as eNOS phosphorylation at S1177. We further reveled that lack of Ng expression decreases both AKT-dependent eNOS phosphorylation, NF-κB-mediated eNOS expression, and promotes endothelial activation. Our findings also indicate that Ng modulates Ca-dependent calcineurin (CaN) activity, which suppresses Ca-independent AKT-dependent eNOS signaling. Moreover, deletion of Ng in mice also reduced eNOS activity and caused endothelial dysfunction in flow-mediated dilation experiments. Our results demonstrate that Ng plays a crucial role in Ca-CaM-dependent eNOS regulation and contributes to vascular remodeling, which is important for the pathophysiology of cardiovascular disease.
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http://dx.doi.org/10.1016/j.redox.2020.101487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327963PMC
July 2020

Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration.

Sci Rep 2019 02 14;9(1):2002. Epub 2019 Feb 14.

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA.

Doxorubicin (Dox) is a highly effective anticancer drug but cause acute ventricular dysfunction, and also induce late-onset cardiomyopathy and heart failure. Despite extensive studies, the pathogenic sequelae leading to the progression of Dox-associated cardiomyopathy remains unknown. We assessed temporal changes in autophagy, mitochondrial dynamics, and bioenergetics in mouse models of acute and chronic Dox-cardiomyopathy. Time course study of acute Dox-treatment showed accumulation of LC3B II in heart lysates. Autophagy flux assays confirmed that the Dox-induced accumulation of autophagosomes occurs due to blockage of the lysosomal degradation process. Dox-induced autophagosomes and autolysosome accumulation were confirmed in vivo by using GFP-LC3 and mRFP-GFP-LC3 transgenic (Tg) mice. Mitochondria isolated from acute Dox-treated hearts showed significant suppression of oxygen consumption rate (OCR). Chronic Dox-cardiotoxicity also exhibited time-dependent accumulation of LC3B II levels and increased accumulation of green puncta in GFP-LC3 Tg hearts. Mitochondria isolated from chronic Dox-treated hearts also showed significant suppression of mitochondrial OCR. The in vivo impairment of autophagic degradation process and mitochondrial dysfunction data were confirmed in vitro using cultured neonatal cardiomyocytes. Both acute and chronic Dox-associated cardiomyopathy involves a multifocal disease process resulting from autophagosomes and autolysosomes accumulation, altered expression of mitochondrial dynamics and oxidative phosphorylation regulatory proteins, and mitochondrial respiratory dysfunction.
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http://dx.doi.org/10.1038/s41598-018-37862-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376057PMC
February 2019

Cardiac Dysfunction in the Sigma 1 Receptor Knockout Mouse Associated With Impaired Mitochondrial Dynamics and Bioenergetics.

J Am Heart Assoc 2018 10;7(20):e009775

1 Department of Pathology and Translational Pathobiology Louisiana State University Health Sciences Center Shreveport LA.

Background The Sigma 1 receptor (Sigmar1) functions as an interorganelle signaling molecule and elicits cytoprotective functions. The presence of Sigmar1 in the heart was first reported on the basis of a ligand-binding assay, and all studies to date have been limited to pharmacological approaches using less-selective ligands for Sigmar1. However, the physiological function of cardiac Sigmar1 remains unknown. We investigated the physiological function of Sigmar1 in regulating cardiac hemodynamics using the Sigmar1 knockout mouse (Sigmar1). Methods and Results Sigmar1 hearts at 3 to 4 months of age showed significantly increased contractility as assessed by left ventricular catheterization with stimulation by increasing doses of a β-adrenoceptor agonist. Noninvasive echocardiographic measurements were also used to measure cardiac function over time, and the data showed the development of cardiac contractile dysfunction in Sigmar1 hearts as the animals aged. Histochemistry demonstrated significant cardiac fibrosis, collagen deposition, and increased periostin in the Sigmar1 hearts compared with wild-type hearts. Ultrastructural analysis of Sigmar1 cardiomyocytes revealed an irregularly shaped, highly fused mitochondrial network with abnormal cristae. Mitochondrial size was larger in Sigmar1 hearts, resulting in decreased numbers of mitochondria per microscopic field. In addition, Sigmar1 hearts showed altered expression of mitochondrial dynamics regulatory proteins. Real-time oxygen consumption rates in isolated mitochondria showed reduced respiratory function in Sigmar1 hearts compared with wild-type hearts. Conclusions We demonstrate a potential function of Sigmar1 in regulating normal mitochondrial organization and size in the heart. Sigmar1 loss of function led to mitochondrial dysfunction, abnormal mitochondrial architecture, and adverse cardiac remodeling, culminating in cardiac contractile dysfunction.
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http://dx.doi.org/10.1161/JAHA.118.009775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474981PMC
October 2018

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation-Induced Cardiac Proteotoxicity.

J Am Heart Assoc 2018 07 9;7(14). Epub 2018 Jul 9.

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA

Background: Desmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown.

Methods And Results: Cardiomyocyte-specific overexpression of mutated desmin (a 7 amino acid deletion R172-E178, D7-Des Tg) causes accumulations of electron-dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7-Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7-Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi-1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7-Des overexpression in cardiomyocytes.

Conclusions: Aberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7-Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy-associated cellular dysfunction.
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http://dx.doi.org/10.1161/JAHA.118.009289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064863PMC
July 2018

Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice.

FASEB J 2018 10 26;32(10):5426-5435. Epub 2018 Apr 26.

Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, California, USA.

Infiltration of T cells is associated with patients who have diabetes at an increased risk of heart attack. T-cell sphingosine 1-phosphate receptor 1 (S1P)-mediated signaling directs T-lymphocyte trafficking. Effects of T-cell S1P activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T-cell S1P knockout (TS1PKO) mice generated by crossing S1pr mice with Lck-Cre mice were used in a model of streptozotocin-induced diabetic cardiomyopathy. The TS1PKO mice exhibited sustained deficiency of both CD4 and CD8 T cells in the blood. The TS1PKO vehicle control mouse hearts featured an altered phenotype characterized by increased myocardial fibrosis and reduced cardiac contractility under normal levels of glucose. Compared with littermate diabetic mice, TS1PKO diabetic mice had improved cardiac function and alleviated cardiac fibrosis detected after 11 wk of diabetic induction. Our results indicate that T-cell S1P signaling activation plays a dual role in the pathogenesis of cardiac fibrosis with respect to the levels of glucose: T-cell S1P activation exerts antifibrotic effects in normoglycemia but exacerbates fibrosis under hyperglycemia.-Abdullah, C. S., Jin, Z.-Q. Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice.
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http://dx.doi.org/10.1096/fj.201800231RDOI Listing
October 2018

Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes.

Biosci Rep 2017 Aug 16;37(4). Epub 2017 Jul 16.

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, U.S.A.

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes.
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http://dx.doi.org/10.1042/BSR20170898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518542PMC
August 2017

Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy.

Int Immunopharmacol 2016 Oct 3;39:251-264. Epub 2016 Aug 3.

Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA; Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA 95757, USA. Electronic address:

T cell infiltration has been associated with increased coronary heart disease risk in patients with diabetes mellitus. Effect of modulation of T cell trafficking on diabetes-induced cardiac fibrosis has yet to be determined. Therefore, our aim was to investigate the circulatory T cell depletion-mediated cardioprotection in streptozotocin-induced diabetic cardiomyopathy. Fingolimod (FTY720), an immunomodulatory drug, was tested in wild-type (WT) C57BL/6 and recombination activating gene 1 (Rag1) knockout (KO) mice without mature lymphocytes in streptozotocin-induced type 1 diabetic model. FTY720 (0.3mg/kg/day) was administered intraperitoneally daily for the first 4weeks with interim 3weeks then resumed for another 4weeks in 11weeks study period. T lymphocyte counts, cardiac histology, function, and fibrosis were examined in diabetic both WT and KO mice. FTY720 reduced both CD4(+) and CD8(+) T cells in diabetic WT mice. FTY720-treated diabetic WT mouse myocardium showed reduction in CD3 T cell infiltration and decreased expression of S1P1 and TGF-β1 in cardiac tissue. Fibrosis was reduced after FTY720 treatment in diabetic WT mice. Rag1 KO mice exhibited no CD4(+) and CD8(+) T cells in the blood and CD3 T cells in the heart. Diabetic Rag1 KO mouse hearts appeared no fibrosis and exhibited preserved myocardial contractility. FTY720-induced antifibrosis was abolished in diabetic Rag1 KO mice. These findings demonstrate that chronic administration with FTY720 induces lymphopenia and protects diabetic hearts in WT mice whereas FTY720 increases cardiac fibrosis and myocardial dysfunction in diabetic Rag1 KO mice without mature lymphocytes.
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http://dx.doi.org/10.1016/j.intimp.2016.07.027DOI Listing
October 2016

Inhibition of PKC-θ preserves cardiac function and reduces fibrosis in streptozotocin-induced diabetic cardiomyopathy.

Br J Pharmacol 2014 Jun;171(11):2913-24

Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD, USA.

Background And Purpose: T-cell infiltration, interstitial fibrosis and cardiac dysfunction have been observed in diabetic patients with cardiovascular diseases. PKC-θ is crucial for the activation of mature T-cells. We hypothesized that inhibition of PKC-θ might protect diabetic hearts through inhibition of T-cell stimulation and maintenance of tight junction integrity.

Experimental Approach: A model of type 1 diabetes was induced by streptozotocin (STZ) (50 mg kg(-1) for 5 days) in male C57BL/6J wild-type (WT) mice and Rag1 knockout (KO) mice which lack mature lymphocytes. A cell-permeable selective PKC-θ peptide inhibitor (PI) was administered i.p. (0.2 mg kg(-1) ·day(-1) ) for 4 weeks (first phase) and 2 weeks (second phase). At the end of the 11th week, cardiac contractile force was measured in isolated perfused hearts. Cardiac morphology and fibrosis were determined. Phosphorylation of PKC-θ at Tyr(358) , infiltrated T-cells and tight junction protein ZO-1 within the hearts were detected, using immunohistochemcial techniques.

Key Results: PI did not affect high blood glucose level in both WT and Rag1 KO diabetic mice. Diabetes induced cardiac fibrosis in WT mice but not in Rag1 KO mice. PI attenuated cardiac fibrosis and improved cardiac contractility of WT diabetic hearts. PI decreased expression of phosphorylated PKC-θ, reduced the infiltration of T-cells and increased ZO-1 expression within WT diabetic hearts.

Conclusion And Implications: Inhibition of PKC-θ improves cardiac function and reduces cardiac fibrosis in WT mice with streptozotocin-induced diabetes. Mature T-cells play a key role in pathophysiology of diabetic cardiomyopathy.
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http://dx.doi.org/10.1111/bph.12621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243864PMC
June 2014
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