Abstract
β3-adrenergic receptor (AR) and the downstream signaling, nitric oxide synthase (NOS) isoforms, have been emerged as novel modulators of heart function and even potential therapeutic targets for cardiovascular diseases. However, it is not known whether β3-AR plays cardioprotective effects against myocardial infarction (MI) injury. Therefore, the present study was designed to determine the effects of β3-AR on MI injury and to elucidate the underlying mechanism. MI model was constructed by left anterior descending (LAD) artery ligation. Animals were administrated with β3-AR agonist BRL37344 (BRL) or β3-AR inhibitor SR59230A (SR) respectively at 0.1 mg/kg/hour one day after MI operation. The scar area, cardiac function and the apoptosis of myocardial were assessed by Masson's trichrome stain, echocardiography and TUNEL assay respectively. Western blot analysis was performed to elucidate the expressions of target proteins. β3-AR activation with BRL administration significantly attenuated fibrosis and decreased scar area after MI. Moreover, BRL also preserved heart function, and reduced the apoptosis of cardiomyocyte induced by MI. Furthermore, BRL treatment altered the phosphorylation status of endothelial NOS (eNOS) and increased the expression of neuronal NOS (nNOS). These results suggested that β3-AR stimulation has a substantial effect on recovery of heart function. In addition, the activations of both eNOS and nNOS may be associated with the cardiac protective effects of β3-AR.
Highlights
Despite a wide range of therapeutic approaches, myocardial infarction (MI) continues to be one of the leading cause of death worldwide [1,2,3]
We found that b3-adrenergic receptor (AR) activation decreased the apoptosis of cardiomyocytes and inhibited fibrosis, which contributed to the enhanced cardiac function after MI
Our data revealed a novel mechanism by which endothelial NOS (eNOS) and neuronal NOS (nNOS) pathways were related with the protective effect of b3-AR
Summary
Despite a wide range of therapeutic approaches, myocardial infarction (MI) continues to be one of the leading cause of death worldwide [1,2,3]. We have previously demonstrated that b3-AR2/2 mice exhibited exacerbated pathological remodeling and impaired cardiac functional [10] These results suggested that b3-AR may play a protective role in pathological remodeling and in the development of heart failure. There is accumulating evidence suggesting that b3-AR plays an important role in the modulation of cardiovascular function in heart failure that. These effects may be associated with nitric oxide (NO) release via nitric oxide synthase (NOS) activation [13]. MI is associated with sustained overactivation of sympathetic nervous system, which results in an increased b3-AR stimulus (ie, catecholamines) It is not known whether b3-AR plays cardiac-protective effects against MI injury. We designed the present study to explore the potential role of b3-AR in cardiac physiology and pathobiology during MI and to elucidate the underline mechanism
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