Aerobic Exercise Inhibits Sympathetic Nerve Sprouting and Restores β-Adrenergic Receptor Balance in Rats with Myocardial Infarction

Abstract

BackgroundCardiac sympathetic nerve sprouting and the dysregulation of β-adrenergic receptor (β-AR) play a critical role in the deterioration of cardiac function after myocardial infarction (MI). Growing evidence indicates that exercise provides protection against MI. The aims of this study were to investigate whether aerobic exercise following MI could inhibit sympathetic nerve sprouting and restore the balance of β3-AR/β1-AR.MethodsMale Sprague-Dawley rats were divided into three groups: sham-operated control group (SC), MI group (MI), and MI with aerobic exercise group (ME). The rats in ME group were assigned to 8 weeks of exercise protocol (16 m/min, 50 min/d, 5 d/wk). The expression of nerve growth factor (NGF), the sympathetic nerve marker-tyrosine hydroxylase (TH), the nerve sprouting marker-growth associated protein 43 (GAP43), and β1- and β2-AR expression in the peri-infarct area of the left ventricle (LV) were measured by Western blot and immunohistochemistry, while β3-AR expression was determined by Western blot and immunofluorescence. Endothelial nitric oxide synthase (NOS2), phospho-NOS2 (p-NOS2), and neuronal nitric oxide synthase (NOS1) were measured by Western blot.ResultsMI increased LV end-diastolic pressure (LVEDP), and decreased LV systolic pressure (LVSP). Compared with the MI group, aerobic exercise significantly decreased LVEDP and increased LVSP. The protein expression of TH, GAP43 and NGF was significantly increased after MI, which was normalized by exercise. Compared with the SC group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were elevated in the MI group, and the protein expression of β3-AR and NOS1 increased after MI. Compared with the MI group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were normalized in the ME group, while the protein expression of β3-AR and NOS1 significantly increased, and NOS2 was activated by exercise.ConclusionsAerobic exercise inhibits cardiac sympathetic nerve sprouting, restores β3-AR/β1-AR balance and increases β3-AR expression through the activation of NOS2 and NOS1 after myocardial infarction.

Exercise training on cardiovascular diseases: Role of animal models in the elucidation of the mechanisms

“…Moreover, authors observed increased activation of NO synthase 1 (NOS1) and NOS2 in the heart of animals submitted to PE, indicating possible modulation of β3-AR through NO pathway. Therefore, considered together, these results indicate that the protective effect of PE in MI can be modulated by β3-AR/NO pathway 79 .…”

“…However, animal studies have shown that if PE starts as soon as possible after MI this can further improve heart function, increasing maximum stroke volume, ejection fraction and attenuating the deterioration of LV contractility. These beneficial effects may be associated with PE-induced proliferation of cardiomyocytes, angiogenesis, attenuation of apoptosis in cardiomyocytes, due to improvement of myofilaments and management of intracellular calcium (Ca 2+ ) 79 .…”

“…On the other hand, Chen et al 79 , assuming that several evidences indicate that PE decreases sympathetic activity after MI, investigated whether such phenomenon occurred by inhibition of sympathetic nerve sprouting and restoring of β3-AR/β1-AR ratio.…”

“…Activation of β3-AR induces NO production, which, in turn, is associated with NOS1 activity. NOS1 signaling leads to increased cardiac calcium cycling, followed by enhanced cardiac contraction and accelerated relaxation 79 .…”

CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury

“…Taken together, these data demonstrate that, although CITED4 expression does not confer acute cardioprotection, it does markedly mitigate adverse remodeling after ischemic injury. Since exercise training has independent beneficial effects on both initial infarct size and late adverse remodeling (38), we infer that CITED4-independent pathways mediate the former, while CITED4-dependent pathways are likely major contributors to the latter. Adverse remodeling is an important cause of human heart failure that may be more amenable to therapeutic targeting than initial infarct size, given the unanticipated nature of acute coronary syndromes.…”