scholarly journals Calpain-mediated protein targets in cardiac mitochondria following ischemia–reperfusion

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Ling Li ◽  
Jeremy Thompson ◽  
Ying Hu ◽  
Edward J. Lesnefsky ◽  
Belinda Willard ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Large Subunit ◽  
Cardiac Injury ◽  
Cysteine Proteases ◽  
Complex Iii ◽  
Regulatory Subunit ◽  
Protein Targets

AbstractCalpain 1 and 2 (CPN1/2) are calcium-dependent cysteine proteases that exist in cytosol and mitochondria. Pharmacologic inhibition of CPN1/2 decreases cardiac injury during ischemia (ISC)–reperfusion (REP) by improving mitochondrial function. However, the protein targets of CPN1/2 activation during ISC–REP are unclear. CPN1/2 include a large subunit and a small regulatory subunit 1 (CPNS1). Genetic deletion of CPNS1 eliminates the activities of both CPN1 and CPN2. Conditional cardiomyocyte specific CPNS1 deletion mice were used in the present study to clarify the role of CPN1/2 activation in mitochondrial damage during ISC–REP with an emphasis on identifying the potential protein targets of CPN1/2. Isolated hearts from wild type (WT) or CPNS1 deletion mice underwent 25 min in vitro global ISC and 30 min REP. Deletion of CPNS1 led to decreased cytosolic and mitochondrial calpain 1 activation compared to WT. Cardiac injury was decreased in CPNS1 deletion mice following ISC–REP as shown by the decreased infarct size compared to WT. Compared to WT, mitochondrial function was improved in CPNS1 deletion mice following ischemia–reperfusion as shown by the improved oxidative phosphorylation and decreased susceptibility to mitochondrial permeability transition pore opening. H2O2 generation was also decreased in mitochondria from deletion mice following ISC–REP compared to WT. Deletion of CPNS1 also resulted in less cytochrome c and truncated apoptosis inducing factor (tAIF) release from mitochondria. Proteomic analysis of the isolated mitochondria showed that deletion of CPNS1 increased the content of proteins functioning in regulation of mitochondrial calcium homeostasis (paraplegin and sarcalumenin) and complex III activity. These results suggest that activation of CPN1 increases cardiac injury during ischemia–reperfusion by impairing mitochondrial function and triggering cytochrome c and tAIF release from mitochondria into cytosol.

A novel human small subunit of calpains

2002 ◽  
Vol 362 (2) ◽  
pp. 383-388 ◽  
Author(s):  
Éva SCHÁD ◽  
Attila FARKAS ◽  
Gáspár JÉKELY ◽  
Peter TOMPA ◽  
Peter FRIEDRICH
Keyword(s):  
Expressed Sequence Tag ◽  
Large Subunit ◽  
Cysteine Proteases ◽  
Small Subunit ◽  
Regulatory Subunit ◽  
Intronless Gene ◽  
Functional Equivalent

Typical calpains are heterodimeric cysteine proteases which have distinct large catalytic subunits (80kDa) but share a common small regulatory subunit (30kDa; css1). Here we report the identification, cloning and characterization of a novel human small subunit (css2) encoded by an intronless gene, capns2, located on chromosome 16. This new protein displays 73% sequence identity within the Ca2+-binding region but lacks two oligo-Gly stretches characteristic of the N-terminal domain of the conventional small subunit. css2 appears to be the functional equivalent of the conventional small subunit in vitro in that it helps the large subunit fold into the active conformation of similar Ca2+ sensitivity when the two proteins are co-expressed in Escherichia coli. The purification of various chimaeric rat 80kDa—human css2 constructs, on the other hand, shows that css2 binds the large subunit much more weakly than css1. Further, it does not undergo the autolytic conversion typical of the classical small subunit. The expression of this protein in vivo, as assessed from its appearance in expressed sequence tag clones, is rather limited, making it an example of a tissue-specific, rather than ubiquitous, small subunit.

scholarly journals Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
He Tai ◽  
Xiao-lin Jiang ◽  
Zhi-ming Lan ◽  
Yue Li ◽  
Liang Kong ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cell Apoptosis ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Abdominal Cavity ◽  
Myocardial Cell ◽  
Renal Ischemia ◽  
Tanshinone Iia ◽  
Obese Rats

Abstract Background Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Methods Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined. Results TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam). Conclusion We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.

Abstract 203: Regulation of Lipid Phosphate Phosphatase 3 in Cardiac Ischemia/Reperfusion Injury and Hypertrophy

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Mini Chandra ◽  
Jonathan Fox ◽  
Wayne Orr ◽  
Christopher Kevil ◽  
Sumitra Miriyala ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Negative Regulator ◽  
Cardiomyocyte Hypertrophy ◽  
Acute Mi ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphatases ◽  
Old Mice

Generation of reactive oxygen species (ROS) has been implicated in myocardial infarction (MI), stroke and sudden cardiac death. Mitochondrial respiration is a major source of ROS production and lipids regulate mitochondrial oxidative metabolism and homeostasis through effects on mitochondrial fusion and fission and on the activity of mitochondrial membrane proteins. Lipid phosphate phosphatases (LPPs) control the conversion of bioactive lipid phosphates to their dephosphorylated counterparts. These include phosphatidic acid (PA), and lysophosphatidic acid (LPA). Oxidative stress was identified to transactivate microRNA-92a, which is a negative regulator of LPP3. We found that LPP3 expression was markedly down regulated in ischemic regions after ischemia/reperfusion (I/R) injury. We observed a similar trend in the myocardium from patients with acute MI at 24h. Our in vitro studies indicate that overexpression of LPP3 protects the cardiomyocyte against ROS-induced cardiac injury and reduction of LPP3 by conditional specific cardiac knockout of the LPP3 gene in mice increases cardiac dysfunction and mortality. These mice are viable and fertile but showed increased mortality ~8 months (Fig1). Blood pressure was similar in LPP3 fl/fl (96 ± 9 mmHg; n = 19) and Myh6- LPP3 Δ mice (92 ± 7 mmHg; n = 19), although heart rates were significantly higher in Myh6- LPP3 Δ 3 month old mice (642 ± 21 bpm, compared to LPP3 fl/fl with 600± 17 bpm; P<0.001). Knockdown of LPP3 enhanced cardiomyocyte hypertrophy induced by LPA based on analysis of sarcomere organization, cell surface area, levels of fetal genes ANP and BNP, and ANF release from nuclei, which are hallmarks of cardiomyocyte hypertrophy, indicating that LPP3 negatively regulates cardiomyocyte hypertrophy induced by LPA.

scholarly journals Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

2015 ◽  
Vol 112 (17) ◽  
pp. E2253-E2262 ◽  
Author(s):  
Youn Wook Chung ◽  
Claudia Lagranha ◽  
Yong Chen ◽  
Junhui Sun ◽  
Guang Tong ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mouse Heart ◽  
Targeted Disruption

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B−/− heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B−/− mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B−/− mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca2+-induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B−/− heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3–enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.

Evaluation of Mitochondrial Function in Isolated Rat Hepatocytes and Mitochondria during Oxidative Stress

2007 ◽  
Vol 35 (3) ◽  
pp. 353-361 ◽  
Author(s):  
Zuzana Červinková ◽  
Halka Lotková ◽  
Pavla Křivaková ◽  
Tomáš Roušar ◽  
Otto Kučera ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Mitochondrial Permeability Transition ◽  
Energy Requirement ◽  
High Energy ◽  
Molecular Probe ◽  
Isolated Rat Hepatocytes ◽  
Isolated Mitochondria

The majority of toxic agents act either fully or partially via oxidative stress, the liver, specifically the mitochondria in hepatocytes, being the main target. Maintenance of mitochondrial function is essential for the survival and normal performance of hepatocytes, which have a high energy requirement. Therefore, greater understanding of the role of mitochondria in hepatocytes is of fundamental importance. Mitochondrial function can be analysed in several basic models: hepatocytes cultured in vitro; mitochondria in permeabilised hepatocytes; and isolated mitochondria. The aim of our study was to use all of these approaches to evaluate changes in mitochondria exposed in vitro to a potent non-specific peroxidating agent, tert-butylhydroperoxide (tBHP), which is known to induce oxidative stress. A decrease in the mitochondrial membrane potential (MMP) was observed in cultured hepatocytes treated with tBHP, as illustrated by a significant reduction in Rhodamine 123 accumulation and by a decrease in the fluorescence of the JC-1 molecular probe. Respiratory Complex I in the mitochondria of permeabilised hepatocytes showed high sensitivity to tBHP, as documented by high-resolution respirometry. This could be caused by the oxidation of NADH and NADPH by tBHP, followed by the disruption of mitochondrial calcium homeostasis, leading to the collapse of the MMP. A substantial decrease in the MMP, as determined by tetraphenylphosphonium ion-selective electrode measurements, also confirmed the dramatic impact of tBHP-induced oxidative stress on mitochondria. Swelling was observed in isolated mitochondria exposed to tBHP, which could be prevented by cyclosporin A, which is evidence for the role of mitochondrial permeability transition. Our results demonstrate that all of the above-mentioned models can be used for toxicity assessment, and the data obtained are complementary.

scholarly journals Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia/reoxygenation injuries

2017 ◽  
Vol 114 (23) ◽  
pp. E4582-E4591 ◽  
Author(s):  
Xiju He ◽  
Shoutian Li ◽  
Benju Liu ◽  
Sebastian Susperreguy ◽  
Karina Formoso ◽  
...  
Keyword(s):  
Calcium Release ◽  
Transient Receptor Potential ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Permeability Transition ◽  
Transient Receptor Potential Channels ◽  
Trpc Channels ◽  
Potential Channels

The injury phase after myocardial infarcts occurs during reperfusion and is a consequence of calcium release from internal stores combined with calcium entry, leading to cell death by apoptopic and necrotic processes. The mechanism(s) by which calcium enters cells has(ve) not been identified. Here, we identify canonical transient receptor potential channels (TRPC) 3 and 6 as the cation channels through which most of the damaging calcium enters cells to trigger their death, and we describe mechanisms activated during the injury phase. Working in vitro with H9c2 cardiomyoblasts subjected to 9-h hypoxia followed by 6-h reoxygenation (H/R), and analyzing changes occurring in areas-at-risk (AARs) of murine hearts subjected to a 30-min ischemia followed by 24-h reperfusion (I/R) protocol, we found: (i) that blocking TRPC with SKF96365 significantly ameliorated damage induced by H/R, including development of the mitochondrial permeability transition and proapoptotic changes in Bcl2/BAX ratios; and (ii) that AAR tissues had increased TUNEL+ cells, augmented Bcl2/BAX ratios, and increased p(S240)NFATc3, p(S473)AKT, p(S9)GSK3β, and TRPC3 and -6 proteins, consistent with activation of a positive-feedback loop in which calcium entering through TRPCs activates calcineurin-mediated NFATc3-directed transcription of TRPC genes, leading to more Ca2+ entry. All these changes were markedly reduced in mice lacking TRPC3, -6, and -7. The changes caused by I/R in AAR tissues were matched by those seen after H/R in cardiomyoblasts in all aspects except for p-AKT and p-GSK3β, which were decreased after H/R in cardiomyoblasts instead of increased. TRPC should be promising targets for pharmacologic intervention after cardiac infarcts.

Baicalein attenuates oxidant stress in cardiomyocytes

2002 ◽  
Vol 282 (3) ◽  
pp. H999-H1006 ◽  
Author(s):  
Zuo-Hui Shao ◽  
Terry L. Vanden Hoek ◽  
Yimin Qin ◽  
Lance B. Becker ◽  
Paul T. Schumacker ◽  
...  
Keyword(s):  
Cell Death ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
Complex Iii ◽  
Ros Generation ◽  
Resonance Spectroscopy ◽  
Iodide Uptake ◽  
Simulated Ischemia

Flavonoids within Scutellaria baicalensis may be potent antioxidants on the basis of our studies of S. baicalensis extract. To further this work, we studied the antioxidative effects of baicalein, a flavonoid component of S. baicalensis, in a chick cardiomyocyte model of reactive oxygen species (ROS) generation during hypoxia, simulated ischemia-reperfusion, or mitochondrial complex III inhibition with antimycin A. Oxidant stress was measured by oxidation of the intracellular probes 2′,7′-dichlorofluorescin diacetate and dihydroethidium. Viability was assessed by propidium iodide uptake. Baicalein attenuated oxidant stress during all conditions studied and acted within minutes of treatment. For example, baicalein given only at reperfusion dose dependently attenuated the ROS burst at 5 min after 1 h of simulated ischemia. It also decreased subsequent cell death at 3 h of reperfusion from 52.3 ± 2.5% in untreated cells to 29.4 ± 3.0% (with return of contractions; P < 0.001). In vitro studies using electron paramagnetic resonance spectroscopy with the spin trap 5-methoxycarbonyl-5-methyl-1-pyrroline- N-oxide revealed that baicalein scavenges superoxide but does not mimic the effects of superoxide dismutase. We conclude that baicalein can scavenge ROS generation in cardiomyocytes and that it protects against cell death in an ischemia-reperfusion model when given only at reperfusion.

scholarly journals Inhibition of Mitochondrial Complex III in Candida Albicans ADH1 Deletion Mutant Attenuates Its Pathogenicity Significantly

2021 ◽  
Author(s):  
Hui Guo ◽  
Yi Shan Zhang ◽  
Yan Jun Song ◽  
Ya Jing Zhao ◽  
Shui Xiu Li ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Alternative Oxidase ◽  
Oxidase Inhibitor ◽  
Complex Iii ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Aerobic Growth ◽  
Transport Chain ◽  
Atp Generation

Abstract Fermentation and aerobic respiration in mitochondria are coordinately regulated and compensated either when C. albicans grows in vitro or in the hosts, and the creature gain the strong viability. It’s insufficient to influent the growth, reproduction and pathogenicity of C. albicans by inhibiting the electron transport chain (ECT) CI, CII, CIII, CV, or fermentation related gene ADH1. Our study showed that the induction of AA (inhibitor of complex III) rather than SHAM (alternative oxidase inhibitor) abolishes the mitochondrial function completely （96% less ATP generation, 59% reduction in MMP), and increases ROS production significantly in ADH1-deleted mutant ( adh1Δ/ adh1Δ ) that in turn becomes hypersensitive to azole and apoptosis, less viable and more difficult to form hyphae. At the same time, the expression of virulence related genes ALS3 and HWP1 were significantly lower than that of WT under AA induction. Under the induction of AA, the mitochondrial function of WT was slightly damaged and cell apoptosis increased slightly，ROS production and sensitivity of azoles increased significantly, but mycelium formation and the growth of cells were not affected. Under aerobic growth, we observed an ADH1 - dependent mitochondrial effect in C. albicans demonstrated by 64% less ATP generation, 58% reduction in MMP and significant elevations of the ROS and apoptosis in ADH1 -deleted mutant. However, mycelium formation and azole susceptibility are not affected. Our results suggested that ADH1 plus CIII played an important role in antifungal activity by damaging mitochondrial function, inhibiting cell growth and hyphae formation, promoting apoptosis and reducing pathogenicity.

scholarly journals special feature: from in vitro curiosity to contributor to cell pathology

2006 ◽  
Vol 28 (4) ◽  
pp. 33-36
Author(s):  
Meredith F. Ross ◽  
Michael P. Murphy
Keyword(s):  
Mitochondrial Function ◽  
Matrix Protein ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Ischaemia Reperfusion Injury ◽  
Mitochondrial Inner Membrane ◽  
Biochemical Journal

The MPT (mitochondrial permeability transition) occurs when a protein pore opens in the mitochondrial inner membrane in response to calcium overloading, adenine nucleotide depletion and oxidative stress, causing the disruption of mitochondrial function. For a number of years, this intriguing phenomenon was thought to be an in vitro curiosity of uncertain relevance to mitochondrial function within cells and tissues. However, this view was fundamentally altered with the help of three papers published in the Biochemical Journal in the 1980s and 1990s. Together, these studies demonstrated that CsA (cyclosporin A) selectively blocked induction of the MPT, that the mitochondrial matrix protein cyclophilin D was required for induction of the MPT, and that the MPT contributed to tissue damage during IR (ischaemia–reperfusion) injury.

scholarly journals Tanshinone IIA Combined With CsA Inhibit Myocardial Cell Apoptosis Induced by Renal Ischemia-reperfusion Injury by Modulating Mitochondrial Function Through PI3K/Akt/Bad Pathway in Obese Rats 

2020 ◽  
Author(s):  
He Tai ◽  
Xiao-lin Jiang ◽  
Yue Li ◽  
Liang Kong ◽  
Si-cheng Yao ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cell Apoptosis ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Cell ◽  
Renal Ischemia ◽  
Tanshinone Iia ◽  
Mitochondrial Dynamic ◽  
Obese Rats

Abstract Background: Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Methods: Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. Related indicators were examined.Results: TIIA combined with CsA alleviated the pathohistological injury and apoptosis induced by renal IR in myocardial cells. In addition, TIIA combined with CsA improved cardiac function and decreased the serum myocardial enzyme spectrum in obese rats after renal IR. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in the respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes (Ⅰ, Ⅱ, Ⅲ, Ⅳ, and Ⅴ). The injury of mitochondrial dynamic function was assessed by a decrease in Drp1, and increases in Mfn1 and Mfn2, and mitochondrial biogenesis injury was assessed by decreases in PGC-1, NRF1, and TFam. TIIA combined with CsA can attenuate apoptosis through modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.Conclusion: We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.

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