Selective inhibition of p38α MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury

2006 ◽  
Vol 291 (4) ◽  
pp. H1972-H1977 ◽  
Author(s):  
Zhihe Li ◽  
Jing Ying Ma ◽  
Irene Kerr ◽  
Sarvajit Chakravarty ◽  
Sundeep Dugar ◽  
...  
Keyword(s):  
Cardiac Function ◽  
P38 Mapk ◽  
Rat Model ◽  
Myocardial Injury ◽  
Myocardial Damage ◽  
Cardiomyocyte Apoptosis ◽  
Ang Ii ◽  
P38α Mapk ◽  
Cardioprotective Effects ◽  
Mapk Inhibitor

p38 MAPK is activated during heart diseases that might associate with myocardial damage and deterioration of cardiac function. In a rat model of myocardial injury, we have investigated cardioprotective effects of the inhibition of p38 MAPK using a novel, orally available p38α MAPK inhibitor. Rats were treated with Nω-nitro-l-arginine methyl ester (l-NAME, 40 mg·kg−1·day−1) in drinking water plus 1% salt for 14 days and ANG II (0.5 mg·kg−1·day−1) for 3 days. A selective p38α MAPK inhibitor, SD-282 (60 mg/kg), was administrated orally, twice a day for 4 days, starting 1 day before ANG II administration. The cardioprotective effects of p38α MAPK inhibition were evaluated by improvement of cardiac function, reduction of inflammatory cell infiltration, and cardiomyocyte apoptosis. SD-282 significantly improved cardiac function indicated by increasing stroke volume, cardiac output, ejection fraction, and stroke work and significantly decreasing arterial elastance. SD-282 also significantly reduced macrophage infiltration as judged by reduction of a specific marker, ED-1-positive staining cells ( P < 0.05) in the myocardium. Furthermore, cardiomyocyte apoptosis as indicated by caspase-3 immunohistochemical staining was abolished by SD-282, and this effect may contribute to the reduction of myocardial damage evaluated by imaging analysis ( P < 0.05 in both cases). Data suggest that p38α MAPK may play a critical role in the pathogenesis of cardiac dysfunction. Inhibition of p38α MAPK may be used as a novel cardioprotective strategy in attenuation of inflammatory response and deterioration of cardiac function that occurs in acute cardiovascular disease such as myocardial infarction.

Hypertrophied myocardium is vulnerable to ischemia/reperfusion injury and refractory to rapamycin-induced protection due to increased oxidative/nitrative stress

2018 ◽  
Vol 132 (1) ◽  
pp. 93-110 ◽  
Author(s):  
Lei-Lei Ma ◽  
Yang Li ◽  
Pei-Pei Yin ◽  
Fei-Juan Kong ◽  
Jun-Jie Guo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Coronary Artery Ligation ◽  
Nitrative Stress ◽  
Cardioprotective Effects

Left ventricular hypertrophy (LVH) is causally related to increased morbidity and mortality following acute myocardial infarction (AMI) via still unknown mechanisms. Although rapamycin exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury in normal animals, whether rapamycin-elicited cardioprotection is altered in the presence of LVH has yet to be determined. Pressure overload induced cardiac hypertrophied mice and sham-operated controls were exposed to AMI by coronary artery ligation, and treated with vehicle or rapamycin 10 min before reperfusion. Rapamycin produced marked cardioprotection in normal control mice, whereas pressure overload induced cardiac hypertrophied mice manifested enhanced myocardial injury, and was refractory to rapamycin-elicited cardioprotection evidenced by augmented infarct size, aggravated cardiomyocyte apoptosis, and worsening cardiac function. Rapamycin alleviated MI/R injury via ERK-dependent antioxidative pathways in normal mice, whereas cardiac hypertrophied mice manifested markedly exacerbated oxidative/nitrative stress after MI/R evidenced by the increased iNOS/gp91phox expression, superoxide production, total NO metabolites, and nitrotyrosine content. Moreover, scavenging superoxide or peroxynitrite by selective gp91phox assembly inhibitor gp91ds-tat or ONOO− scavenger EUK134 markedly ameliorated MI/R injury, as shown by reduced myocardial oxidative/nitrative stress, alleviated myocardial infarction, hindered cardiomyocyte apoptosis, and improved cardiac function in aortic-banded mice. However, no additional cardioprotective effects were achieved when we combined rapamycin and gp91ds-tat or EUK134 in ischemic/reperfused hearts with or without LVH. These results suggest that cardiac hypertrophy attenuated rapamycin-induced cardioprotection by increasing oxidative/nitrative stress and scavenging superoxide/peroxynitrite protects the hypertrophied heart from MI/R.

Licorice treatment prevents oxidative stress, restores cardiac function, and salvages myocardium in rat model of myocardial injury

2013 ◽  
Vol 31 (2) ◽  
pp. 140-152 ◽  
Author(s):  
Shreesh Kumar Ojha ◽  
Charu Sharma ◽  
Mahaveer Jain Golechha ◽  
Jagriti Bhatia ◽  
Santosh Kumari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Rat Model ◽  
Myocardial Injury

scholarly journals Inhibiting Cardiac Mitochondrial Fatty Acid Oxidation Attenuates Myocardial Injury in a Rat Model of Cardiac Arrest

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Peng Wang ◽  
Fan Zhang ◽  
Liming Pan ◽  
Yunke Tan ◽  
Fengqing Song ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Rat Model ◽  
Myocardial Injury ◽  
Myocardial Damage ◽  
Acid Oxidation ◽  
Ros Generation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid

Mitochondrial fatty acid oxidation (FAO) is involved in myocardial damage after cardiopulmonary resuscitation (CPR). This study is aimed at investigating the effect of inhibiting mitochondrial FAO on myocardial injury and the underlying mechanisms of postresuscitation myocardial dysfunction. Rats were induced, subjected to 8 min of ventricular fibrillation, and underwent 6 min of CPR. Rats with return of spontaneous circulation (ROSC) were randomly divided into the Sham group, CPR group, and CPR + Trimetazidine (TMZ) group. Rats in the CPR + TMZ group were administered TMZ (10 mg/kg) at the onset of ROSC via the right external jugular vein, while rats in the CPR group were injected with equivalent volumes of vehicle. The sham rats were only administered equivalent volumes of vehicle. We found that the activities of enzymes related to cardiac mitochondrial FAO were partly improved after ROSC. TMZ, as a reversible inhibitor of 3-ketoacyl CoA thiolase, inhibited myocardial mitochondrial FAO after ROSC. In the CPR + TMZ group, the levels of mitochondrial injury in cardiac tissue were alleviated following attenuated myocardial damage and oxidative stress after ROSC. In addition, the disorder of cardiac mitochondrial metabolism was ameliorated, and specifically, the superfluous succinate related to mitochondrial reactive oxygen species (ROS) generation was decreased by inhibiting myocardial mitochondrial FAO with TMZ administration after ROSC. In conclusion, in the early period after ROSC, inhibiting cardiac mitochondrial FAO attenuated excessive cardiac ROS generation and preserved myocardial function, probably by alleviating the dysfunction of cardiac mitochondrial metabolism in a rat model of cardiac arrest.

scholarly journals MicroRNA-322-5p Protects Against Myocardial Infarction through Targeting BTG2

2021 ◽  
Author(s):  
Yang Ruan ◽  
Shuai Meng ◽  
Ruofei Jia ◽  
Xiaojing Cao ◽  
zening Jin
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
B Cell ◽  
Rat Model ◽  
Myocardial Injury ◽  
Pathological Condition ◽  
Current Paper ◽  
Targeted Treatment ◽  
Myocardial Tissue

Abstract Objective: A large cohort of studies have addressed the therapeutic importance of microRNA (miR) in the treatment of myocardial infarction (MI). The current paper gives prominence to the role of miR-322-5p in MI by regulating B-cell translocation gene 2 (BTG2).Methods: In a rat model of MI miR-322-5p and BTG2 expression was estimated. Adenovirus that altered miR-322-5p or BTG2 expression was injected into MI rats. After that, cardiac function, inflammation, myocardial injury, pathological condition, apoptosis, and the NF-κB pathway-related genes in the myocardial tissue of MI rats after targeted treatment were evaluated. The targeting relationship between miR-322-5p and BTG2 was assessed.Results: miR-322-5p was lowly expressed and BTG2 was highly expressed in the myocardial tissue of MI rats. Restored miR-322-5p improved cardiac function, relived inflammation and myocardial injury, suppressed pathological condition and apoptosis and inactivated NF-κB pathway in MI rats. BTG2 expression was negatively mediated by miR-322-5p. Overexpressed BTG2 rescued miR-322-5p-induced cardioprotection on MI rats.Conclusion: It is evident that miR-322-5p protects against MI through suppressing BTG2 expression.

scholarly journals Heat Shock Protein 70 Protects the Heart from Ischemia/Reperfusion Injury through Inhibition of p38 MAPK Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Nan Song ◽  
Jiao Ma ◽  
Xiao-wen Meng ◽  
Hong Liu ◽  
Hui Wang ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Heat Shock Protein 70 ◽  
Myocardial Injury ◽  
Cell Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Myocardial Infarct Size ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background. Heat shock protein 70 (Hsp70) has been shown to exert cardioprotection. Intracellular calcium ([Ca2+]i) overload induced by p38 mitogen-activated protein kinase (p38 MAPK) activation contributes to cardiac ischemia/reperfusion (I/R) injury. However, whether Hsp70 interacts with p38 MAPK signaling is unclear. Therefore, this study investigated the regulation of p38 MAPK by Hsp70 in I/R-induced cardiac injury. Methods. Neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation for 6 h followed by 2 h reoxygenation (OGD/R), and rats underwent left anterior artery ligation for 30 min followed by 30 min of reperfusion. The p38 MAPK inhibitor (SB203580), Hsp70 inhibitor (Quercetin), and Hsp70 short hairpin RNA (shRNA) were used prior to OGD/R or I/R. Cell viability, lactate dehydrogenase (LDH) release, serum cardiac troponin I (cTnI), [Ca2+]i levels, cell apoptosis, myocardial infarct size, mRNA level of IL-1β and IL-6, and protein expression of Hsp70, phosphorylated p38 MAPK (p-p38 MAPK), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2), phosphorylated signal transducer and activator of transcription3 (p-STAT3), and cleaved caspase3 were assessed. Results. Pretreatment with a p38 MAPK inhibitor, SB203580, significantly attenuated OGD/R-induced cell injury or I/R-induced myocardial injury, as evidenced by improved cell viability and lower LDH release, resulted in lower serum cTnI and myocardial infarct size, alleviation of [Ca2+]i overload and cell apoptosis, inhibition of IL-1β and IL-6, and modulation of protein expressions of p-p38 MAPK, SERCA2, p-STAT3, and cleaved-caspase3. Knockdown of Hsp70 by shRNA exacerbated OGD/R-induced cell injury, which was effectively abolished by SB203580. Moreover, inhibition of Hsp70 by quercetin enhanced I/R-induced myocardial injury, while SB203580 pretreatment reversed the harmful effects caused by quercetin. Conclusions. Inhibition of Hsp70 aggravates [Ca2+]i overload, inflammation, and apoptosis through regulating p38 MAPK signaling during cardiac I/R injury, which may help provide novel insight into cardioprotective strategies.

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