RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

Background/Aims: Oxidative stress is strongly implicated in the pathogenesis of myocardial damage caused by ischemia reperfusion (I/R). Previous studies have confirmed that cardiac CD47 drives left ventricular heart failure. However, the role for CD47 in myocardial I/R injury (MIRI) has not previously been proposed. This study was designed to investigate whether down-regulation of CD47 using RNA interference (RNAi) technology can relieve inhibition of nitric oxide signaling and attenuate myocardial damage in a rat model of I/R. Methods: Male Sprague-Dawley rats (n = 40) were randomly allocated to four groups and pre-treated either with saline (Sham and I/R groups), or adenovirus expressing either control (Ad-EGFP-N) or CD47-targeting (Ad-EGFP-CD47) RNAi. After four days, the rat MIRI model was established by occluding the left anterior descending coronary artery for 30 min, followed by reperfusion for 3 h. Heart tissue was harvested and assessed by immunohistochemistry, western blot, and quantitative RT-PCR. Outcome measures included infarct size, myocardial enzyme (creatine kinase, creatine kinase-MB, and lactate dehydrogenase) levels in serum, markers of oxidative stress, and morphological changes to the myocardium. Results: Delivery of Ad-EGFP-CD47 RNAi into the myocardium remarkably decreased CD47 expression levels. Down-regulation of CD47 was significantly associated with reduced infarct size and serum levels of myocardial enzymes, increased activity of endothelial nitric oxide synthase, increased levels of nitric oxide, and decreased levels of oxidative stress. Conclusion: These data indicate that down-regulation of CD47 exerts a protective effect against MIRI, which may be attributable to attenuation of oxidative stress via activation of the eNOS/NO signaling pathway.

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Protective Effect of Swertiamarin on Myocardial Injury Through Activation of Nrf2/HO-1 Pathway in Heart Failure Model of Rats

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:260-265 ◽

2020 ◽

Vol 18 (3) ◽

pp. 260-265

Author(s):

Xu Lin ◽

Zheng Xiaojun ◽

Lv Heng ◽

Mo Yipeng ◽

Tong Hong

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Ejection Fraction ◽

Protective Effect ◽

Infarct Size ◽

Rat Model ◽

Left Ventricular ◽

Related Factor ◽

Nuclear Factor ◽

Internal Dimension

The purpose of this study was to evaluate the protective effect of swertiamarin on heart failure. To this end, a rat model of heart failure was established via left coronary artery ligation. Infarct size of heart tissues was determined using triphenyl tetrazolium chloride staining. Echocardiography was performed to evaluate cardiac function by the determination of ejection fraction, left ventricular internal dimension in diastole and left ventricular internal dimension in systole. The effect of swertiamarin on oxidative stress was evaluated via enzyme-linked immunosorbent assay. The mechanism was evaluated using western blot. Administration of swertiamarin reduced the infarct size of heart tissues in rat models with heart failure. Moreover, swertiamarin treatment ameliorated the cardiac function, increased ejection fraction and fractional shortening, decreased left ventricular internal dimension in diastole and left ventricular internal dimension in systole. Swertiamarin improved oxidative stress with reduced malondialdehyde, while increased superoxide dismutase, glutathione, and GSH peroxidase. Furthermore, nuclear-factor erythroid 2-related factor 2, heme oxygenase and NAD(P)H dehydrogenase (quinone 1) were elevated by swertiamarin treatment in heart tissues of rat model with heart failure. Swertiamarin alleviated heart failure through suppression of oxidative stress response via nuclear-factor erythroid 2-related factor 2/heme oxygenase-1 pathway providing a novel therapeutic strategy for heart failure.

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Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00844.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. H542-H550 ◽

Cited By ~ 22

Author(s):

Toshihiro Shinbo ◽

Kenichi Kokubo ◽

Yuri Sato ◽

Shintaro Hagiri ◽

Ryuji Hataishi ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiac Function ◽

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Neutrophil Infiltration ◽

Left Ventricular ◽

Hydrogen Gas ◽

Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

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Local anesthetic Ropivacaine protects rats from myocardial ischemia/reperfusion injury by inhibition of COX-2

Archives of Medical Science ◽

10.5114/aoms/132472 ◽

2021 ◽

Author(s):

Zhou Yu ◽

Sufang Sun ◽

Fang Hu

Keyword(s):

Oxidative Stress ◽

Creatine Kinase ◽

Ischemia Reperfusion ◽

Inos Expression ◽

Ischaemic Injury ◽

Cardiac Tissues ◽

Tnf Α ◽

Creatine Kinase Mb ◽

Cellular Apoptosis ◽

Cox 2

IntroductionMyocardial ischaemia/reperfusion (I/R) injury is the leading cause of morbidity and mortality worldwide. Despite novel advances in therapeutics, the management of myocardial I/R is still an unmet medical need. Therefore, in the present study, we have demonstrated the protective effect of ropivacaine (RPC) on the myocardial infarction in rats and its underlying mechanism.Material and methodsInitially, the effect of RPC was determined on the infarct size and histopathology of cardiac tissues. The effect of RPC was also determined on the levels of various cardiac biomarkers such as creatine kinase (CK), creatine kinase MB (CK-MB), alanine aminotransferase (ALT), asparganine aminotransferase (AST), and lactate dehydrogenase (LDH), and biomarkers of oxidative stress (MDA, SOD, and GSH) and inflammation (tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and IL-6). RPC effect was also quantified on cellular apoptosis and COX-2 and iNOS expression via western blot analysis. The RPC was further docked into the active site of COX-2.ResultsIt has been found that RPC reduces the improves haemodynamics of (LVSP and ± dp/dtmax, and LVEDP), infarct percentage and architecture of cardiac tissues of rats. It also reduces the level of studies cardiac injury biomarkers together with a reduction of oxidative stress (MDA, SOD, and GSH) and inflammation (TNF-α, IL-1β, and IL-6). Upon administration of RPC, the rate of cellular apoptosis was found to be greatly reduced, with a reduction in COX-2 and iNOS expression. In docking analysis, RPC creates van der Waals forces and pi-interactions with Tyr381, Arg106, Val102, Leu345, Val509, Ser339, Leu338, Val335, Ala513, His75, and Leu517 at the catalytic site of COX-2.ConclusionsCollectively, our results demonstrated that ropivacaine showed significant benefit against myocardial ischaemic injury.

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Angiotensin II type 1 receptor blocker preserves tolerance to ischemia-reperfusion injury in Dahl salt-sensitive rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.91533.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. H2473-H2479 ◽

Cited By ~ 9

Author(s):

Seiji Matsuhisa ◽

Hajime Otani ◽

Toru Okazaki ◽

Koji Yamashita ◽

Yuzo Akita ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Angiotensin Ii ◽

Nitric Oxide Synthase ◽

Infarct Size ◽

Rat Heart ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Oxide Synthase

Oxidative stress is involved in the tolerance to ischemia-reperfusion (I/R) injury. Because angiotensin II type 1 receptor blockers (ARBs) inhibit oxidative stress, there is concern that ARBs abolish the tolerance to I/R injury. Dahl salt-sensitive (DS) hypertensive and salt-resistant (DR) normotensive rats received an antioxidant, 2-mercaptopropionylglycine (MPG), or an ARB, losartan, for 7 days. Losartan and MPG significantly inhibited oxidative stress as determined by tissue malondialdehyde + 4-hydroxynoneal and increased expression of inducible nitric oxide synthase (iNOS) in the DS rat heart. However, losartan but not MPG activated endothelial nitric oxide synthase (eNOS) as assessed by phosphorylation of eNOS on Ser1177. Infarct size after 30-min left coronary artery occlusion followed by 2-h reperfusion was comparable between DS and DR rat hearts. Although MPG and losartan had no effect on infarct size in the DR rat heart, MPG but not losartan significantly increased infarct size in the DS rat heart. A selective iNOS inhibitor, 1400W, increased infarct size in the DS rat heart, but it had no effect on infarct size in the losartan-treated DS rat heart. However, a nonselective NOS inhibitor, Nω-nitro-l-arginine methyl ester, increased infarct size in the losartan-treated DS rat heart. These results suggest that losartan preserves the tolerance to I/R injury by activating eNOS despite elimination of redox-sensitive upregulation of iNOS and iNOS-dependent cardioprotection in the DS rat heart.

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Abstract 1396: Mitigation Of Cardiac Injury By Sulfaphenazole, A CYP2C9 Inhibitor Through Involvement Of Inducible Nitric Oxide Synthase (iNOS) in Post-ischemic Heart

Circulation ◽

10.1161/circ.116.suppl_16.ii_287 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Mahmood Khan ◽

Iyyapu K Mohan ◽

Damodhar Kumbala ◽

Vijay K Kutala ◽

Periannan Kuppusamy

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Infarct Size ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Control Group ◽

Myocardial Tissue ◽

Cytochrome P450 Enzymes ◽

Superoxide Generation ◽

Oxide Synthase

Cytochrome P450 enzymes play a significant role in ischemia-reperfusion (I/R) injury. Sulfaphenazole (SFZ), a potent CYP2C9 inhibitor, is known to reduce I/R injury. However, the mechanism of its cardioprotective effects and the role of nitric oxide (NO) is not clear. Objective : Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of I/R injury. The objective of this study was to determine how SFZ treatment modulates myocardial tissue oxygenation (pO 2 ) and RNS generation in vivo . Methods: Myocardial infarction was induced in rats by ligating the left anterior descending coronary artery (LAD) for 30 min, followed by 24 h of reperfusion. The study was divided into 4 groups: Untreated I/R control, SFZ, L-NAME, and SFZ+L-NAME. L-NAME (100 mg/kg/day), a nitric oxide synthase inhibitor, was given orally for 3 days prior to LAD ligation. SFZ (1.5 mg/kg, ip) was injected 30 min prior to LAD ligation. Oxygen-sensing crystals were implanted into the LV wall and the rat was placed in an L-band (1.2 GHz) electron paramagnetic resonance (EPR) spectrometer for measurement of myocardial tissue pO 2 during I/R injury. Hemodynamic data was collected with a microtip catheter. Infarct size was measured after 24 h of reperfusion. Superoxide generation was determined by dihydroethidium fluorescence imaging. Immunohistological staining was performed for nitrotyrosine and iNOS. Results: After LAD ligation, pO 2 decreased from 18 mmHg baseline to <2 mmHg. At reperfusion, there was a significant myocardial hyperoxygenation in SFZ-treated rats compared to control group (45.0±1.3 vs. 34.0±2.0 mmHg, P<0.05). In L-NAME and L-NAME+SFZ-treated rats, there was a significant reduction in pO 2 (24.0±1.6 and 26.0±2.3 mmHg, respectively). Compared to control, SFZ treatment significantly improved the left ventricular developed pressure (94.0±4.7 vs. 69.0±6.5 mmHg, P<0.05), decreased infarct size % (35.0±4.2 vs. 16.0±2.5, P<0.05), decreased superoxide generation and nitrotyrosine production. Conclusions: These findings demonstrate that SFZ may provide potent cardioprotection by attenuating post-ischemic ROS and RNS generation, and could serve as an attractive adjuvant therapy in the clinical setting of myocardial I/R injury.

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Abstract 17348: Necrostatin 7 Limits Myocardial Infarct Size and Reduces Cardiac Remodeling After Permanent Coronary Occlusion in Rats

Circulation ◽

10.1161/circ.130.suppl_2.17348 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yuri Dmitriev ◽

Sarkis Minasian ◽

Anna Dracheva ◽

Andrey Karpov ◽

Svetlana Chefu ◽

...

Keyword(s):

Infarct Size ◽

Rat Model ◽

Coronary Occlusion ◽

Ventricular Remodeling ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Morphological Characteristics ◽

Left Ventricular ◽

Myocardial Infarct Size

Background: Reduction of irreversible myocardial ischemia-reperfusion injury (IRI) remains important. One of the promising strategies aimed at myocardial IRI alleviation is modulation of programmed cell death (PCD) pathways. PCD mode displaying morphological characteristics of necrosis, and amenable to pharmacological manipulation is referred to as necroptosis. Necroptosis inhibitor necrostatin-1 has been shown to exert cardio- and neuroprotective effects. In the present work, the effect of necrostatin-7 (Nec-7) on myocardial injury in the rat model of permanent coronary occlusion was studied. Methods: Male Wistar rats (n = 19) were anesthetized with pentobarbital. The animals were subjected to permanent coronary occlusion (PCO) and intraperitoneal (i.p.) Nec-7 administration 1 h prior to PCO at a dose of 14.5 mg/kg in dimethyl sulfoxide (DMSO) or DMSO alone at a dose of 3.1 g/kg. Control rats were treated with saline. Three weeks after PCO, serum levels of NT-proBNP were measured, and histological outcomes were assessed. The infarct size (IS, %) and infarct length (IL, mm) were analyzed morphometrically. Results: DMSO caused significant reduction in serum NT-proBNP level vs. Control (0.3 ± 0.19 vs. 0.5 ± 0.22 ng/ml, p = 0.001), while Nec-7 further decreased NT-proBNP level in comparison with DMSO (0.2 ± 0.14 ng/ml, p = 0.008 vs. DMSO). Compared with Control, DMSO reduced adverse left ventricular remodeling, as evidenced by reduction in IS (16.0 ± 2.92 and 12.9 ± 1.72%, p = 0.015) and IL (6.2 ± 0.89 and 3.8 ± 0.35 mm, p = 0.008). Nec-7 treatment resulted in additional reduction of both IS and IL vs. DMSO group (9.0 ± 4.91 % and 2.9 ± 1.62 mm, respectively; p = 0.013 and p = 0.011 vs. DMSO, respectively). Conclusion: Nec-7 has cardioprotective properties, reducing myocardial wall stress and myocardial remodeling in the rat model of myocardial infarction.

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The Relationship between Cardiotrophin-1 and Troponin-I in Coronary Arterial Bypass Grafting on the Beating Heart: A Prospective Study

The Heart Surgery Forum ◽

10.1532/hsf.1386 ◽

2015 ◽

Vol 18 (4) ◽

pp. 146 ◽

Cited By ~ 1

Author(s):

Serhat Caliskan ◽

Feyzullah Besli ◽

Fatih Gungoren ◽

Ahmet Yildirim ◽

Mehmet Fethi Alisir ◽

...

Keyword(s):

Creatine Kinase ◽

Troponin I ◽

Ischemia Reperfusion ◽

Artery Bypass ◽

White Blood Cells ◽

Myocardial Damage ◽

Beating Heart ◽

Creatine Kinase Mb ◽

Opcab Surgery ◽

The Relationship

Objective: Cardiotrophin-1 (CT-1) is closely associated with many cardiovascular diseases, such as hypertension, myocardial infarction (MI), and heart failure, and exhibits a cardioprotective effect in ischemia-reperfusion injury. The aim of this study was to evaluate the relationship between CT-1 and Troponin-I (Tn-I) in off-pump coronary artery bypass (OPCAB) grafting on the beating heart.<br />Methods: Seventy-eight patients (mean age 60.8 ± 9.7 years, 79.5% male) undergoing elective OPCAB surgery were included in this study undertaken between July 1, 2012 and July 1, 2013 in the Department of Cardiology and Cardiac Surgery, University School of Medicine Hospital. Venous blood samples were collected 5 minutes before OPCAB surgery and 6 hours after surgery. Plasma CT-1 levels were measured using the ELISA method.<br />Results: Compared to the preoperative period, Tn-I and CT-1 values were higher in the postoperative period <br />[0.255 ng/mL (0.030-0.430) versus 0.045 ng/mL (0.005-0.090), P < .001; and 33.7 pg/mL (15.8-98.5) versus 8.7 pg/mL (0.68-25.4), P < .001]. There was also an elevation in white blood cells, aspartate aminotransferase, creatine kinase (CK), and creatine kinase MB (CK-MB) values, as well as a decrease in hemoglobin values (P < .001). When a correlation analysis for postoperative CT-1 was performed, there was a significant positive correlation between postoperative CK, CK-MB, and Tn-I levels (r = 0.250, P < .027; r = 0.270, P = .017; and r = 0.241, P < .034).<br />Conclusion: CT-1 was found to be associated with Tn-I, which is used to detect myocardial damage after OPCAB surgery. CT-1 may also be used to detect myocardial damage.

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Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00064.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. H1545-H1552 ◽

Cited By ~ 14

Author(s):

Yilong Fu ◽

Zhongjing Wang ◽

Woei Lee Chen ◽

Philip K. Moore ◽

Yi Zhun Zhu

Keyword(s):

Nitric Oxide ◽

Myocardial Ischemia ◽

Infarct Size ◽

Ischemia Reperfusion ◽

Myocardial Damage ◽

Tween 80 ◽

Vehicle Group ◽

Lv Function ◽

Cardioprotective Effects ◽

Cox 2

In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg·kg−1·day−1), and NO-aspirin (56 mg·kg−1·day−1). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle ( n = 23), aspirin ( n = 22), and NO-aspirin groups ( n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 ± 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 ± 1.8 and 22.9 ± 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemiareperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with NG-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. l-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.

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Abstract 3379: Feasibility Of Adrenomedullin Infusion In Patients With Acute Myocardial Infarction -a Possible Cardioprotective Therapy Against Ischemic Injury-

Circulation ◽

10.1161/circ.116.suppl_16.ii_762-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Satoshi Yasuda ◽

Shunichi Miyazaki ◽

Noritoshi Nagaya ◽

Yu Kataoka ◽

Teruo Noguchi ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Infarct Size ◽

Intravenous Administration ◽

Ischemia Reperfusion ◽

Coronary Intervention ◽

Reperfusion Therapy ◽

Left Ventricular ◽

Stress Generation

Background : Adrenomedullin (ADM) is a 52-amino-acid vasodilator peptide that was originally isolated from human pheochromocytoma. In the previous experimental study with rat ischemia/reperfusion model, ADM reduced infarct size and inhibited myocyte apoptosis. ADM also suppressed the production of oxygen-free-radicals. The present study was designed to evaluate the feasibility of intravenous administration of ADM in patients with acute myocardial infarction (AMI). Methods : We studied 10 patients with first AMI (M/F;9/1, mean age;65 years, peak CPK level; 4090 U/L[median]), who were hospitalized within 12 hours of symptom onset. ADM infusion preceded percutaneous coronary intervention (PCI) and was continued at concentration of 0.0125 − 0.025μg/kg/minute for 12 hours. We also studied 10 control AMI patients matched for age, sex and infarct size, who did not receive ADM. Results : During ADM infusion, hemodynamics kept stable except one patient with right ventricular infarction. Urinary levels of 8-iso-prostaglandine F2α, which was measured after the reperfusion therapy with ADM infusion as a marker of oxidative stress, was significantly lower in patients who received ADM than those who did not (76 ± 40 vs 174±21 pmol/mol of creatinine, P<0.01). Infarct area (IA) evaluated by magnetic resonance imaging and brain natriuretic peptide (BNP) levels were also different between the two groups (Table ). Conclusions : Intravenous administration of ADM, which possesses a variety of cardiovascular protective actions, is feasible and can be adjunctive to PCI. Suppression of oxidative stress generation may be beneficial for attenuation of left ventricular dysfunction and remodeling following AMI.

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Abstract 13725: Oxidative Stress Accelerates Senescence and Reduces Life Span but Does Not Alter Cardioprotection in Mice Over-expressing H11kinase/hsp22

Circulation ◽

10.1161/circ.130.suppl_2.13725 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Didier Morin ◽

Romain Long ◽

Lydie Laure ◽

Christophe Depre ◽

Stephen F Vatner ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Hypertrophy ◽

Infarct Size ◽

Life Span ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Left Ventricular Cavity ◽

Ventricular Ejection Fraction

H11 kinase/Hsp22 (H11K) is a small heat shock protein which provides powerful cardioprotection, i.e., reduction by 80% of infarct size expressed as a fraction of area at risk following 45 min coronary occlusion/4 hr reperfusion when over-expressed in a cardiac-specific transgenic (TG) mouse model. The goal of this investigation was to determine if these protective mechanisms would also enhance longevity and be effective in protecting from age-related myocardial dysfunction. Surprisingly, TG mice showed a reduction of 48% in their mean life span as compared to wild type (WT). The mechanism of premature death was most likely cardiac as left ventricular ejection fraction was reduced in one year old TG mice (49% vs 74% in WT, p<0.01), left ventricular cavity was dilated and cardiac hypertrophy was increased by 58%, all compatible with severe dilated cardiomyopathy. At the molecular level, hearts from TG mice showed a significant increase in reactive oxygen species, oxidized/reduced glutathione ratio, NADPH and xanthine oxidase activities, Nox2 expression associated with an increase in p16, p19 mRNA, β-galactosidase positive cells and telomerase activity. Subgroups of WT and TG mice were also treated with the antioxidant tempol (100 mg/kg/d) from weaning to their sacrifice. Chronic tempol treatment abolished oxidative stress, reduced cardiac hypertrophy, extended life span (+31%) and prevented aging markers (p16, p19 mRNA, β-galactosidase positive cells) in TG mice. The marked reduction in infarct size with ischemia/reperfusion noted above, observed in 10-12 weeks old mice, remained unchanged after tempol in TG mice and was not abolished with aging. Thus, this is the first demonstration that the mechanisms mediating reduced longevity such as increased oxidative stress do not reduce cardioprotection in H11K TG mice, and conversely, the mechanisms mediating powerful cardioprotection against ischemic stress are ineffective in maintaining normal cardiac function with aging.

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