LOX-1 abrogation reduces myocardial ischemia-reperfusion injury in mice

LOX-1 is a newly described lectin-like receptor for oxidized-LDL (ox-LDL), which is over-expressed in the ischemic myocardium. To examine the pathogenic role of LOX-1 in the determination of ischemia-reperfusion (I-R) injury to the heart, we developed LOX-1 knockout (KO) mice, and subjected these mice to 60 min of left coronary artery occlusion followed by 60 min of reperfusion. I-R in the LOX-1 KO mice resulted in a significant reduction in myocardial injury as well as in accumulation of inflammatory cells in the I-R myocardium and lipid peroxidation (P < 0.01 vs. wild-type mice). Concomitantly, there was significant preservation of cardiac function in the LOX-1 KO mice despite I-R (P < 0.01 vs. the wild-type mice). The phosphorylation of oxidative stress-sensitive mitogen-activated protein kinase (p38MAPK) and protein kinase B/Akt-1, expression of nitrotyrosine and inducible nitric oxide synthase (iNOS), and superoxide dismutase activity were enhanced during I-R in the wild-type mice. These alterations in p38MAPK, Akt-1 and iNOS were much less pronounced in the LOX-1 KO mice. The superoxide dismutase activity increased further in the LOX-1 KO mice. These observations provide compelling evidence that LOX-1 may be a key modulator of myocardial I-R injury, and its effect is mediated by pro-oxidant signals. LOX-1 may be a potential target for therapy of myocardial ischemic injury.     

Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo

Accumulating evidence indicates that programmed necrosis plays a critical role in cell death during ischemia-reperfusion. Necrostatin-1 (Nec-1), a small molecule capable of inhibiting a key regulator of programmed necrosis (RIP1), was shown to prevent necrotic cell death in experimental models including cardiac ischemia. However, no functional follow-up was performed and the action of Nec-1 remains unclear. Here, we studied whether Nec-1 inhibits RIP1-dependent necrosis and leads to long-term improvements after ischemia-reperfusion in vivo. Mice underwent 30 min of ischemia and received, 5 min before reperfusion, 3.3 mg/kg Nec-1 or vehicle treatment, followed by reperfusion. Nec-1 administration reduced infarct size to 26.3 ± 1.3% (P = 0.001) compared to 38.6 ± 1.7% in vehicle-treated animals. Furthermore, Nec-1 inhibited RIP1/RIP3 phosphorylation in vivo and significantly reduced necrotic cell death, while apoptotic cell death remained constant. By using MRI, cardiac dimensions and function were assessed before and 28 days after surgery. Nec-1-treated mice displayed less adverse remodeling (end-diastolic volume 63.5 ± 2.8 vs. 74.9 ± 2.8 μl, P = 0.031) and preserved cardiac performance (ejection fraction 45.81 ± 2.05 vs. 36.03 ± 2.37%, P = 0.016). Nec-1 treatment significantly reduced inflammatory influx, tumor necrosis factor-α mRNA levels and oxidative stress levels. Interestingly, this was accompanied by significant changes in the expression signature of oxidative stress genes. Administration of Nec-1 at the onset of reperfusion inhibits RIP1-dependent necrosis in vivo, leading to infarct size reduction and preservation of cardiac function. The cardioprotective effect of Nec-1 highlights the importance of necrotic cell death in the ischemic heart, thereby opening a new direction for therapy in patients with myocardial infarction.     

Effect of nitrates on myocardial remodeling after acute myocardial infarction

Nitrates are effective for the therapy of acute coronary syndromes, including acute myocardial infarction. Their application in acute infarction has established that vasodilators are beneficial provided hypotension is avoided. Nitrates limit early ventricular remodeling in infarction. New dosing strategies and formulations that permit chronic use after infarction with less tolerance might limit late remodeling. Over the last decade, the demonstrated effectiveness of angiotensin-converting enzyme (ACE) inhibitors in limiting ventricular dilation postinfarction has generated controversy over the usefulness of nitrates for that indication. The uncertainty has been intensified by 2 large mortality trials that tested both agents as adjuncts to conventional therapy. These trials were not designed to test whether nitrates might limit remodeling. Mechanistic experimental and clinical studies that tested whether nitrates or ACE inhibitors could effectively limit ventricular remodeling showed that both improved remodeling endpoints. However, experimental studies raise some concern about the decrease in infarct collagen associated with ACE inhibition and emphasize the fact that final outcome represents a balance of effects. That nitrates do not decrease infarct collagen could be important. Nitrate-induced early recruitment of ventricular function after late reperfusion of acute infarction might also be important. In the mortality trials, > 50% of patients received open-label nitrates as per indication. Thus, the trial results to date do not suggest that nitrates are ineffective for remodeling, but rather that ACE inhibitors can confer added benefit. There has been no large clinical trial to test the efficacy of nitrates for remodeling as there has been for ACE inhibitors.     

Cardiac remodeling after myocardial infarction is impaired in IGF-1 deficient mice

OBJECTIVE: To obtain more insight in the role of IGF-1 in cardiac remodeling and function after experimental myocardial infarction. We hypothesized that cardiac remodeling is altered in IGF-1 deficient mice, which may affect cardiac function. METHODS: A myocardial infarction was induced by surgical coronary artery ligation in heterozygous IGF-1 deficient mice. One week after surgery, left ventricular function was analyzed, and parameters of cardiac remodeling were measured. RESULTS: No significant difference in cardiac function was found between infarcted wildtype and knock-out animals, despite a marked reduction in capillarization and blunting of the hypertrophic response of the interventricular septum in the IGF-1 deficient group. Furthermore, decreased DNA synthesis and increased apoptosis rates were observed in the IGF-1 knock-out mice. CONCLUSION: IGF-1 deficient mice show preservation of cardiac function 1 week after MI, despite an altered cardiac remodeling process.     

Ventricular "remodeling" after myocardial infarction

Cardiac failure is the principal medium-term complication of myocardial infarction. Changes in left ventricular geometry are observed after infarction, called ventricular remodeling, which, though compensatory initially, cause ventricular failure in the long-term. Experimental and clinical studies suggest that early treatment by coronary recanalisation, trinitrin and angiotensin converting enzyme inhibitors may prevent or limit the expansion and left ventricular dilatation after infarction, so improving ventricular function, and, at least in the animal, reduce mortality. Large scale trials with converting enzyme inhibitors are currently under way to determine the effects of this new therapeutic option. It would seem possible at present, independently of any reduction in the size of the infarction, to reduce or delay left ventricular dysfunction by interfering with the natural process of dilatation and ventricular modeling after infarction.     

Left ventricular remodeling after myocardial infarction in mice with targeted deletion of the NADPH oxidase subunit gp91PHOX

Background Oxidative stress is involved in progression of left ventricular hypertrophy and heart failure. Since NADPH oxidases are a major source of reactive oxygen species in the heart, we studied left ventricular remodeling after myocardial infarction in mice with targeted deletion of the NADPH oxidase subunit gp91^phox. Methods and results gp91^phox knockout (KO) and wild–type (WT) animals underwent coronary artery ligation. Mortality was significant higher in the gp91^phox KO mice. However, transthoracic echocardiography performed at days 1, 7, and 56 at mid–papillary levels revealed that progression of left ventricular remodeling was not influenced by the genotype. Moreover, systemic oxidative stress was not reduced in gp91^phox KO mice as indicated by a significant increase in lipid peroxides potentially mediated by an increase of the NADPH subunit nox–1 in gp91^phox KO mice. Conclusion Targeted deletion of the NADPH subunit gp91^phox does not affect left ventricular remodeling following myocardial infarction and does not decrease the production of oxidative stress. However, the final role of the different NADPH subunits in the heart under pathophysiologic conditions remains to be determined.     

Prevention of left ventricular remodeling after myocardial infarction

Opinion statement Postinfarction left ventricular remodeling begins early after acute myocardial infarction and may continue for months to years afterward. Early re-establishment of flow in the occluded artery is associated with smaller left ventricular cavity volumes and reduced remodeling. Acute percutaneous coronary intervention (PCI) or thrombolytic therapy (for patients more than 1 hour away from a catheterization facility) as early as possible after symptoms is critical. Late reperfusion (PCI more than 12 hours after infarction) may prove useful, and this will be determined by the results of ongoing clinical trials. Recurrent MI is reduced by antiplatelet agents (aspirin in most patients) and by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Intravenous nitroglycerin may limit early (initial 24 hours) dilatation following infarction, but long-term use in asymptomatic patients is not efficacious. Betaadrenergic receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors have independent efficacy in attenuating the early and late phases of remodeling. The combined use of a beta-blocker and an ACE inhibitor has greater efficacy than either agent alone, provided they are tolerated hemodynamically. Although angiotensin II receptor antagonists have similar efficacy to ACE inhibitors and have fewer side effects, the angiotensin II receptor blockers should be reserved for patients intolerant to ACE inhibitors. In patients requiring diuretic therapy, spironolactone is preferred because of its salutary properties regarding extracellular matrix remodeling, specifically in reducing fibrosis. Surgical revascularization with or without associated mitral valve repair is useful in selected patients with severe ischemic mitral regurgitation or hibernating myocardium. New therapies directed at modulating the remodeling process may focus on manipulating the components of the extracellular matrix to reduce the deleterious impact of this process.     

Positive effect of darbepoetin on peri-infarction remodeling in a porcine model of myocardial ischemia-reperfusion

Erythropoietin (Epo) has anti-apoptotic and pro-angiogenic effects in rodent models of myocardial infarction (MI). We tested the hypothesis that a long-acting Epo derivative (darbepoetin) has a beneficial effect on infarct size and peri-infarct remodeling in a clinically relevant large animal model of ischemia-reperfusion. A human acute MI scenario was simulated in 16 domestic pigs by inflating an angioplasty balloon in the proximal left circumflex (LCx) artery for 60 min. The animals were randomized to darbepoetin 30 microg/kg i.v. or placebo (saline) at the time of reperfusion. Treatment with darbepoetin did not lead to a reduction in the infarct size at 2 weeks as assessed by histology (30.3+/-1.8% of the volume at risk for placebo vs. 33.2+/-2.5% for darbepoetin). However, significant effects were seen in the peri-infarct region. Histological evaluation revealed decreased interstitial fibrosis (6.8+/-0.7% of myocardial sections area vs. 9.6+/-0.7%, p=0.02) and increased average capillary area (106+/-3% of the non-infarcted myocardium vs. 89+/-4%, p=0.003) in the treatment arm in the absence of significant cardiac hypertrophy. This resulted in preserved regional wall motion as assessed by tissue Doppler-derived radial strain (subepicardial radial strain 90.1+/-21.2% for darbepoetin vs. 20.3+/-10.1% for placebo, p<0.05). However, this did not translate to improved wall thickening (126.5+/-6.0% of diastolic thickness for darbepoetin vs. 119.8+/-5.4% for placebo, p=NS). Beneficial effects of darbepoetin to peri-infarct remodeling were observed in a clinically relevant model of ischemia-reperfusion. Although the infarct size was not reduced, there was a limited decrease in interstitial fibrosis, increased capillary area and regional functional improvement in darbepoetin-treated animals.     

基质金属蛋白酶和心肌梗死后心室重构

心肌梗死后心室重构是慢性心力衰竭发展的重要病理基础，延缓或阻止心室重构已成为慢性心力衰竭的主要治疗方法。基质金属蛋白酶是一组与心室胞外基质重构有关的水解酶，抑制基质金属蛋白酶的表达和活性对心室重构的防治有重要意义。     

心肌梗死后左室重构发病机制进展

急性心肌梗死(AMI)是威胁人类健康的重大疾病,心肌梗死(MI)后30 min,部分心肌细胞即发生不可逆的坏死,因此,MI有效救治的时间窗极为短暂,许多患者不能够得到及时有效的治疗,使得MI后心力衰竭(HF)的发生率仍然居高不下。最新调查研究表明,MI后1年HF的发生率约为14.2%。因MI后HF再次入院的患者,1年死亡率高达为45.5%。MI后HF的主要原因是部分心肌细胞坏死,左室重构,心脏扩张,继而引发HF。目前,MI后左室重构的机制尚未完全阐明。本文介绍了AMI后左室重构的发病机制主要进展。