Abstract 405: Inhibition of Class I Histone Deacetylases at Reperfusion Attenuates Ischemia-reperfusion Injury and Modifies Mitochondrial Acetylation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Sverre E Aune ◽  
Donald R Menick
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Mitochondrial Enzymes ◽  
Reperfusion Phase

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, much of the resultant damage occurs as a consequence of reperfusion itself. Previously, we have shown that pretreatment with MS-275, a selective class I histone deacetylase (HDAC) inhibitor, preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Here, we tested the hypothesis that MS-275 treatment at reperfusion reduces LV tissue damage and improves post-ischemic LV contractile function. To do this, hearts from male Sprague-Dawley rats were isolated and perfused ex vivo on a Langendorff perfusion apparatus. A saline-filled balloon was inserted into the left ventricle of the heart to monitor ventricular pressure development throughout the experiment. Hearts were subjected to 30 minutes of ischemia, followed by 60 minutes of reperfusion. MS-275 was administered during the entire reperfusion phase, and resultant functional data were compared to untreated hearts. There was no difference in any metric of pre-ischemic contractile function between groups. 10nM MS-275 administered at reperfusion significantly improved multiple measures of LV function, including dP/dtmax, -dP/dtmax, developed pressure and rate pressure product. We also observed a significant reduction in infarct area of treated hearts compared to control, as measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Unexpectedly, mass spectrometry analysis revealed significant changes in acetylation state of multiple mitochondrial enzymes. Administration of MS-275 during the reperfusion phase of IR is sufficient to partially rescue LV function from reperfusion-induced damage. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion.

Abstract 222: Inhibition Of Class I But Not Class IIb Lysine Deacetylases Is Responsible For Cardioprotection From Ischemia-Reperfusion.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sverre E Aune ◽  
Santhosh K Mani ◽  
Donald R Menick
Keyword(s):  
Contractile Function ◽  
Trichostatin A ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Specific Inhibition ◽  
Isolated Hearts ◽  
Class Iib

Background: While dual inhibition of class I/IIb KDACs protects the mammalian heart from ischemia-reperfusion (IR) injury, class-specific effects have not been examined. Hypothesis: We hypothesized that specific inhibition of class I KDACs would preserve left ventricular (LV) function following IR in isolated hearts. Methods: Male Sprague-Dawley rats (n=4 per group) were injected with vehicle, the class I KDAC inhibitor entinostat, the class IIb inhibitor tubastatin A, or the class I/IIb inhibitor trichostatin A (TSA). After 18 h, hearts were isolated and perfused in Langendorff mode. A saline-filled balloon was placed in the LV to monitor contractile function. Following IR (30/120 min), LV free wall tissue was assayed for activation of pro-survival proteins. Group results are reported vs vehicle as mean±SE. Results: There were no differences between groups in LV function before ischemia. At the end of reperfusion, rate pressure product (mm hg/min) was improved with entinostat (27392±3474, p<0.001) and TSA (22980±3226, p<0.05) vs vehicle (11,352±1977), as were +dP/dt max and -dP/dt max . Most notably, entinostat alone blunted the rise in end diastolic pressure (mm Hg) during reperfusion (18.6±1.4 vs. 45.3±4.1, p<0.001), and completely prevented diastolic contracture (mm Hg) in reperfusion for up to one hour (12.4±2.0 vs pre-ischemia=8.7±1.7, p=0.21). Contractile function was not significantly preserved in hearts treated with tubastatin A. Entinostat reduced phosphorylation at the eNOS inhibitory site, and increased phosphorylation at the eNOS activation site, and Src activation was dramatically reduced. TSA increased activation of Src, p38, and ERK 1/2, and increased phosphorylation of eNOS at both the activation (Ser1177) and inhibition site (Thr495). Tubastatin A reduced activation of p38, ERK 1/2, and eNOS, but not Src. Conclusions: Inhibition of class I KDACs was most effective at preserving contractile function following IR in isolated hearts, notably through prevention of LV contracture during reperfusion. Class I KDAC inhibition may preserve LV function by differentially modulating Src and eNOS activities. These results suggest that the protective effects of KDAC inhibitors in IR can be ascribed to specific inhibition of class I KDACs.

Abstract 363: Class I HDAC Inhibition Causes Selective Activation of Pro-Survival Kinases at Reperfusion in Post-Ischemic Hearts

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Sverre E Aune ◽  
Daniel J Herr ◽  
Donald R Menick
Keyword(s):  
Ischemia Reperfusion ◽  
Class I ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Sprague Dawley ◽  
Nonhistone Proteins ◽  
Risk Pathway ◽  
Gene And Protein Expression ◽  
Class I Hdacs ◽  
Contractile Recovery

Background: Histone deacetylase (HDAC) enzymes inhibit gene expression through chromatin compaction and exacerbate myocyte death following ischemia-reperfusion (IR) in the heart. In our prior study, disinhibition of antioxidant gene and protein expression was achieved through 24 hour pretreatment with entinostat, a class I HDAC inhibitor, and was correlated with improved heart contractile recovery from IR. Additionally, ERK1/2 was phosphorylated, indicating activation of the reperfusion injury survival kinase (RISK) pathway. HDAC inhibitors also enhance posttranslational acetylation of nonhistone proteins through unmasking of acetyltransferase activity, which may influence heart survival from injury. Hypothesis: We hypothesized that inhibition of class I HDACs during reperfusion in postischemic hearts would activate the RISK pathway and improve contractile recovery. Methods: Hearts from male Sprague-Dawley rats (n=4/group) were isolated and perfused in Langendorff mode. Global ischemia was induced by cessation of perfusion for 30 min, followed by 60 min of reperfusion, during which hearts were perfused with vehicle or 10, 100 or 1000 nM entinostat. Results are reported vs vehicle as mean±SE. Results: At the end of reperfusion, rate pressure product (mm hg/min) was improved with 10 nM entinostat (17226±1187, p<0.001) vs vehicle (11024±1810), as were +dP/dtmax, -dP/dtmax, and developed pressure. The improvement in pressure development with 10 nM entinostat was due primarily to prevention of end diastolic dysfunction in reperfusion. LV function was not significantly preserved in hearts treated with 100 or 1000 nM entinostat. Hearts reperfused with 10 nM entinostat showed reduced infarct area (35%) vs vehicle (64%), along with increased shuttling of 14-3-3 protein, Akt and phospho-ERK from cytoplasm to nucleus. These effects were reduced with higher concentrations of inhibitor. Notably, histone acetylation was increased with higher concentrations of entinostat, but not with 10 nM. Conclusions: Inhibition of class I HDACs during reperfusion resulted in specific activation of RISK members without acetylation of histone, indicating that acetyltransferase enzymes may mediate activation of pro-survival kinases in the IR heart.

Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

2018 ◽  
Vol 132 (15) ◽  
pp. 1669-1683 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Lv Function ◽  
Male Wistar Rats ◽  
Group A

Altered cardiac mitochondrial dynamics with excessive fission is a predominant cause of cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although pre-ischemic inhibition of mitochondrial fission has been shown to improve cardiac function in I/R injury, the effects of this inhibitor given at different time-points during cardiac I/R injury are unknown. Fifty male Wistar rats were subjected to sham and cardiac I/R injury. For cardiac I/R injury, rats were randomly divided into pre-ischemia, during-ischemia, and upon onset of reperfusion group. A mitochondrial fission inhibitor, Mdivi-1 (mitochondrial division inhibitor 1) (1.2 mg/kg) was used. During I/R protocols, the left ventricular (LV) function, arrhythmia score, and mortality rate were determined. Then, the heart was removed to determine infarct size, mitochondrial function, mitochondrial dynamics, and apoptosis. Our results showed that Mdivi-1 given prior to ischemia, exerted the highest level of cardioprotection quantitated through the attenuated incidence of arrhythmia, reduced infarct size, improved cardiac mitochondrial function and fragmentation, and decreased cardiac apoptosis, leading to preserved LV function during I/R injury. Mdivi-1 administered during ischemia and upon the onset of reperfusion also improved cardiac mitochondrial function and LV function, but at a lower efficacy than when it was given prior to ischemia. Taken together, mitochondrial fission inhibition after myocardial ischemic insults still exerts cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings indicate its potential clinical usefulness.

scholarly journals Targeting the Cx43 Carboxyl Terminal H2 Domain Preserves Left Ventricular Function Following Ischemia-Reperfusion Injury

2019 ◽  
Author(s):  
Jingbo Jiang ◽  
Joseph A. Palatinus ◽  
Huamei He ◽  
Jegan Iyyathurai ◽  
L. Jane Jourdan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reperfusion Injury ◽  
Ventricular Function ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Left Ventricular ◽  
Therapeutic Peptide

ABSTRACTBackgroundαCT1 is a 25 amino acid therapeutic peptide incorporating the Zonula Occludens-1 (ZO-1)-binding domain of connexin43 (Cx43) that is currently in Phase III clinical testing for healing chronic skin wounds. In preclinical studies in mice, we reported that αCT1 reduces arrhythmias and improves ventricular function following cardiac injury, effects that were accompanied by increases in PKCε phosphorylation of Cx43 at serine 368 (pS368). In this study, we undertake a systematic characterization of the molecular mode-of-action of αCT1 in mitigating the effects of ischemia reperfusion injury on ventricular contractile function.Methods and ResultsTo determine the basis of αCT1-mediated increases in pS368 we undertook tandem mass spectrometry of reactants in an in vitro assay of PKCε phosphorylation, identifying an interaction between negatively charged amino acids in the αCT1 Asp-Asp-Leu-Glu-Iso sequence and positively charged lysines (Lys345, Lys346) in a short α-helical sequence (H2) within the Cx43 CT domain. In silico modeling provided further support of the specificity of this interaction, leading us to conclude that αCT1 has potential to directly interact with both Cx43 and ZO-1. Using surface plasmon resonance, thermal shift and phosphorylation assays, we characterized a series of αCT1 variant peptides, identifying sequences competent to interact with either ZO-1 PDZ2 or the Cx43 CT, but with limited or no ability to bind both polypeptides. Based on this analysis, it was found that only those peptides competent to interact with Cx43, but not ZO-1 alone, resulted in increased pS368 phosphorylation in vitro and in vivo. Moreover, in a mouse model of global ischemia reperfusion injury we determined that pre-ischemic infusion only with those peptides competent to bind Cx43 preserved left ventricular (LV) contractile function following injury. Interestingly, a short 9 amino acid (MW=1110) Cx43-binding variant of the original 25 amino acid αCT1 sequence demonstrated potent LV-protecting effects when infused either before or after ischemic injury.ConclusionsInteraction of αCT1 with the Cx43 CT, but not ZO-1 PDZ2, explains cardioprotection mediated by this therapeutic peptide. Pharmacophores targeting the Cx43 carboxyl terminus could provide a novel translational approach to preservation of ventricular function following ischemic injury.

Abstract 141: Class I Histone Deacetylases Localize to Cardiac Myocyte Mitochondria and Contribute to Ischemia Reperfusion Injury

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Mauhamad Baarine ◽  
Sverre Aune ◽  
Craig C Beeson ◽  
Lauren E Ball ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Hdac Inhibition ◽  
Acetylation State ◽  
Class I Hdacs

Approximately half of the damage done to the heart by a myocardial infarction occurs during reperfusion of the ischemic region while the patient is in the care of the treatment team. While many different adjuvant treatments have been explored in an attempt to attenuate this ischemia-reperfusion (I/R) injury, little progress has been made in translating novel therapies to the clinic. Recently, it was discovered that epigenetic enzymes contribute to reperfusion-induced damage, but little is known about the exact mechanism by which they exacerbate I/R injury. Previously, we have shown that class I histone deacetylase (HDACs) activity acutely exacerbates I/R injury, and that inhibition of class I HDACs with MS-275 (entinostat) preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Notably, this protective effect occurs whether MS-275 is given as a pretreatment or during the reperfusion phase alone. Given the acute nature of this protective effect, we hypothesized that class I HDACs mediate reperfusion injury by modulating the acetylation state of non-histone proteins in signaling cascades that are essential to cell survival. To examine this, hearts from male Sprague-Dawley rats were subjected to ex vivo I/R injury +/- class I HDAC inhibition during reperfusion. We then performed mass spectrometry to analyze the changes in the acetylome between sham and I/R groups with and without class I HDAC inhibition. Unexpectedly, mass spectrometry analysis revealed significant changes in the acetylation state of multiple mitochondrial enzymes. Further biochemical studies show that class I HDACs localize to cardiac mitochondria and may directly modulate mitochondrial acetylation. Interestingly, these effects are correlated with a reduction in the mitochondrial respiratory capacity and mitochondrial oxidative stress during reperfusion. This study is the first to identify a class I HDAC that localizes to the mitochondria and emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion injury.

C-phycocyanin protects against ischemia-reperfusion injury of heart through involvement of p38 MAPK and ERK signaling

2006 ◽  
Vol 290 (5) ◽  
pp. H2136-H2145 ◽  
Author(s):  
Mahmood Khan ◽  
Saradhadevi Varadharaj ◽  
Latha P. Ganesan ◽  
Jagdish C. Shobha ◽  
Madireddi U. Naidu ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Lactate Dehydrogenase ◽  
P38 Mapk ◽  
Ischemia Reperfusion Injury ◽  
Enhanced Recovery ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
Apoptotic Cells

We previously showed that C-phycocyanin (PC), an antioxidant biliprotein pigment of Spirulina platensis (a blue-green alga), effectively inhibited doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. Here we investigated the cardioprotective effect of PC against ischemia-reperfusion (I/R)-induced myocardial injury in an isolated perfused Langendorff heart model. Rat hearts were subjected to 30 min of global ischemia at 37°C followed by 45 min of reperfusion. Hearts were perfused with PC (10 μM) or Spirulina preparation (SP, 50 mg/l) for 15 min before the onset of ischemia and throughout reperfusion. After 45 min of reperfusion, untreated (control) hearts showed a significant decrease in recovery of coronary flow (44%), left ventricular developed pressure (21%), and rate-pressure product (24%), an increase in release of lactate dehydrogenase and creatine kinase in coronary effluent, significant myocardial infarction (44% of risk area), and TdT-mediated dUTP nick end label-positive apoptotic cells compared with the preischemic state. PC or SP significantly enhanced recovery of heart function and decreased infarct size, attenuated lactate dehydrogenase and creatine kinase release, and suppressed I/R-induced free radical generation. PC reversed I/R-induced activation of p38 MAPK, Bax, and caspase-3, suppression of Bcl-2, and increase in TdT-mediated dUTP nick end label-positive apoptotic cells. However, I/R also induced activation of ERK1/2, which was enhanced by PC treatment. Overall, these results for the first time showed that PC attenuated I/R-induced cardiac dysfunction through its antioxidant and antiapoptotic actions and modulation of p38 MAPK and ERK1/2.

scholarly journals PKCβ modulates ischemia-reperfusion injury in the heart

2008 ◽  
Vol 294 (4) ◽  
pp. H1862-H1870 ◽  
Author(s):  
Linghua Kong ◽  
Martin Andrassy ◽  
Jong Sun Chang ◽  
Chun Huang ◽  
Tomohiro Asai ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Stress Responses ◽  
Ischemia Reperfusion Injury ◽  
Enhanced Recovery ◽  
Ischemia Reperfusion ◽  
Homozygous Deletion ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Lv Function ◽  
Wild Type

Protein kinase C-βII (PKCβII) is an important modulator of cellular stress responses. To test the hypothesis that PKCβII modulates the response to myocardial ischemia-reperfusion (I/R) injury, we subjected mice to occlusion and reperfusion of the left anterior descending coronary artery. Homozygous PKCβ-null (PKCβ−/−) and wild-type mice fed the PKCβ inhibitor ruboxistaurin displayed significantly decreased infarct size and enhanced recovery of left ventricular (LV) function and reduced markers of cellular necrosis and serum creatine phosphokinase and lactate dehydrogenase levels compared with wild-type or vehicle-treated animals after 30 min of ischemia followed by 48 h of reperfusion. Our studies revealed that membrane translocation of PKCβII in LV tissue was sustained after I/R and that gene deletion or pharmacological blockade of PKCβ protected ischemic myocardium. Homozygous deletion of PKCβ significantly diminished phosphorylation of c-Jun NH2-terminal mitogen-activated protein kinase and expression of activated caspase-3 in LV tissue of mice subjected to I/R. These data implicate PKCβ in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKCβ may represent a potent strategy to protect the vulnerable myocardium.

Dietary coenzyme Q10 supplement renders swine hearts resistant to ischemia-reperfusion injury

2000 ◽  
Vol 278 (4) ◽  
pp. H1084-H1090 ◽  
Author(s):  
Nilanjana Maulik ◽  
Tetsuya Yoshida ◽  
Richard M. Engelman ◽  
Debasis Bagchi ◽  
Hajime Otani ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Nutritional Supplementation ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Pump System ◽  
Regular Diet

To examine whether nutritional supplementation of coenzyme Q10(CoQ10) can reduce myocardial ischemia-reperfusion injury, a group of swine was fed a regular diet supplemented with CoQ10 (5 mg ⋅ kg− 1 ⋅ day− 1) for 30 days. Another group of pigs that were fed a regular diet supplemented with placebo served as a control. After 30 days, isolated in situ pig hearts were prepared and hearts were perfused with a cardiopulmonary pump system. Each heart was subjected to 15 min of regional ischemia by snaring of the left anterior descending coronary artery, followed by 60 min of hypothermic cardioplegic global ischemia and 120 min of reperfusion. After the experiments were completed, myocardial infarct size was measured by triphenyltrazolium chloride staining methods. Postischemic left ventricular contractile function was better recovered in the CoQ10 group than in the control group of pigs. CoQ10-fed pigs revealed less myocardial infarction and less creatine kinase release from the coronary effluent compared with control pigs. The experimental group also demonstrated a smaller amount of malonaldehyde in the coronary effluent and a higher content of the endogenous antioxidants ascorbate and thiol. Significant induction of the expression of ubiquitin mRNA was also found in the hearts of the CoQ10-fed group. The results of this study demonstrate that nutritional supplementation of CoQ10 renders the hearts resistant to ischemia-reperfusion injury, probably by reducing the oxidative stress.

scholarly journals Environmentally persistent free radicals compromise left ventricular function during ischemia/reperfusion injury

2015 ◽  
Vol 308 (9) ◽  
pp. H998-H1006 ◽  
Author(s):  
Brendan R. Burn ◽  
Kurt J. Varner
Keyword(s):  
Free Radicals ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Halogenated Hydrocarbons ◽  
Lv Function ◽  
Stroke Work

Increases in airborne particulate matter (PM) are linked to increased mortality from myocardial ischemia. PM contains environmentally persistent free radicals (EPFRs) that form as halogenated hydrocarbons chemisorb to transition metal oxide-coated particles, and are capable of sustained redox cycling. We hypothesized that exposure to the EPFR DCB230 would increase cardiac vulnerability to subsequent myocardial ischemia-reperfusion (MI/R) injury. Rats were exposed to DCB230 or vehicle via nose-only inhalation (230 μg max/day) over 30 min/day for 7 days. MI/R or sham MI/R (sham) was initiated 24 h after the final exposure. Following 1 or 7 days of reperfusion, left ventricular (LV) function was assessed and infarct size measured. In vehicle-exposed rats, MI/R injury did not significantly reduce cardiac output (CO), stroke volume (SV), stroke work (SW), end-diastolic volume (EDV), or end-systolic volume (ESV) after 1 day of reperfusion, despite significant reductions in end-systolic pressure (ESP). Preload-recruitable SW (PRSW; contractility) was elevated, presumably to maintain LV function. MI/R 1-day rats exposed to DCB230 also had similarly reduced ESP. Compared with vehicle controls, CO, SV, and SW were significantly reduced in DCB230-exposed MI/R 1-day rats; moreover, PRSW did not increase. DCB230’s effects on LV function dissipated within 8 days of exposure. These data show that inhalation of EPFRs can exacerbate the deficits in LV function produced by subsequent MI/R injury. Infarct size was not different between the MI/R groups. We conclude that inhalation of EPFRs can compromise cardiac function during MI/R injury and may help to explain the link between PM and MI/R-related mortality.

Calpain inhibitor-1 protects the rat heart from ischemia-reperfusion injury: analysis by mechanical work and energetics

2005 ◽  
Vol 288 (4) ◽  
pp. H1690-H1698 ◽  
Author(s):  
Yoshiro Yoshikawa ◽  
Hiroji Hagihara ◽  
Yoshimi Ohga ◽  
Chikako Nakajima-Takenaka ◽  
Ken-ya Murata ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mechanical Energy ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Mechanical Work ◽  
Lv Function ◽  
Calpain Inhibitor ◽  
Lv Volume

We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of α-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion ( n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly ( P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo2) intercepts (PVA-independent Vo2; Vo2 for the total Ca2+ handling in excitation-contraction coupling and basal metabolism) of Vo2-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly ( P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O2 costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of α-fodrin and the immunostaining of 150-kDa products of α-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of α-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca2+ handling by directly inhibiting the proteolysis of α-fodrin.

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