Deletion of Neuropeptide Y Attenuates Cardiac Dysfunction and Apoptosis During Acute Myocardial Infarction.

Wei Huang,Chao Song,Hongli Sun,Pilong Shi,Hanping Qi,Yongsheng Liu,Qianhui Zhang

doi:10.3389/fphar.2019.01268

Wei Huang, Chao Song + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2019.01268

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Abstract

Increasing neuropeptide Y (NPY) has been shown to be a risk factor for cardiovascular diseases. However, its role and mechanism in myocardial infarction (MI) have not yet been fully understood. H9c2 cells and neonatal rat ventricular myocytes with loss of function of NPY and rats with global knockout were used in this study. MI model of rats was induced by the ligation of left coronary artery, and the extent of MI was analyzed through echocardiographic, pathological, and molecular analyses. Our data demonstrated that NPY expression was significantly increased in MI rats and hypoxia/hydrogen peroxide (H2O2)-treated cardiomyocytes. At the same time, NPY-knockout rats exhibited a remarkable decrease in infarct size, serum lactate dehydrogenase activity, cardiomyocyte apoptosis, and caspase-3 expression and activity and a strong improvement in heart contractile function compared with MI rats. Meanwhile, NPY small interfering RNA (siRNA) inhibited the cell apoptosis in H2O2-treated H9c2 cells and hypoxia-treated neonatal rat ventricular myocytes. NPY deletion increased miR-499 expression and decreased FoxO4 expression in MI in vivo and in vitro. Moreover, NPY type 1 receptor antagonist BIBO3304 can reverse miR-499 decrease and FoxO4 increase in H2O2-induced cardiomyocytes. NPY siRNA inhibited cell apoptosis in H2O2-treated H9c2 cells that were reversed by miR-499 inhibitor. Additionally, FoxO4 was validated as the direct target of miR-499. Moreover, BIBO3304 and FoxO4 siRNA significantly increased the cell activity, inhibited the cell apoptosis, and decreased caspase-3 expression and activity in H2O2-treated cardiomyocytes that NPY presented the opposite effect. Collectively, deletion of NPY reduced myocardial ischemia, improved cardiac function, and inhibited cardiomyocyte apoptosis by NPY type 1 receptor–miR-499–FoxO4 axis, which provides a new treatment for MI.

Highlights

Acute myocardial infarction (MI) is a myocardial perfusion obstruction disease, which is one of the leading causes of morbidity and mortality worldwide (Mozaffarian et al, 2016)
We observed a significant increase in heart neuropeptide Y (NPY) mRNA level of 3 days after MI compared with sham rats (Figure 1C)
We found that miR-499 was decreased and FoxO4 was increased in MI in vivo and in vitro, which were reversed by NPY deletion (Figures 6A–E)

Summary

Introduction

Acute myocardial infarction (MI) is a myocardial perfusion obstruction disease, which is one of the leading causes of morbidity and mortality worldwide (Mozaffarian et al, 2016). NPY plays an important role in regulating physiological functions such as emotions, cardiovascular and immune homeostasis, angiogenesis, cardiac remodeling, appetite, gastrointestinal motility, neuroendocrine axis, sympathetic nerve, and vagal nerve conduction (Grundemar and Hakanson, 1993; Wan and Lau, 1995; Shanks and Herring, 2013). NPY is the most abundant neuropeptide in the heart It is found in the postganglionic sympathetic nerve cells, supplying the vascular system, endocardial and myocardial cells, as well as in cardiac ganglia and parasympathetic nerve cells (Gu et al, 1983; McDermott and Bell, 2007). In addition to playing an important role in normal physiological control mechanisms, it is increasingly involved in the pathophysiological processes of cardiovascular diseases

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