Neuropeptide Y mediates cardiac hypertrophy through microRNA-216b/FoxO4 signaling pathway

Abstract

Cardiac hypertrophy (CH) is a major risk factor for heart failure accompanied by maladaptive cardiac remodeling. The role and potential mechanism of neuropeptide Y (NPY) in CH are still unclear. We will explore the role and the mechanism of NPY inactivation (NPY-I) in CH caused by pressure overload. Abdominal aortic constriction (AAC) was used to induce CH model in rats. NPY or angiotensin II (Ang II) was used to trigger CH model in vitro in neonatal rat ventricular myocytes (NRVMs). We found that NPY was increased in the heart and plasma of hypertrophic rats. However, Ang II did not increase NPY expression in cardiomyocytes. NPY-I attenuated CH as decreasing CH-related markers (ANP, BNP and β-MHC mRNA) level, reducing cell surface area, and restoring cardiac function. NPY inactivation increased miR-216b and decreased FoxO4 expression in CH heart. Moreover, NPY decreased miR-216b and increased FoxO4 expression in NRVMs which were reversed by NPY type 1 receptor (NPY1R) antagonist BIBO3304. MiR-216b mimic and FoxO4 siRNA (small interfering RNA) inhibited NPY/Ang II-induced myocardial hypertrophy in vitro. Meanwhile, BIBO3304 reversed the pro-hypertrophy effect of NPY in vitro. Collectively, NPY deficiency attenuated CH by NPY1R-miR-216b-FoxO4 axis. These findings suggested that NPY would be a potential therapeutic target for the prevention and treatment of cardiac hypertrophy.

Neuropeptide Y as a risk factor for cardiorenal disease and cognitive dysfunction in chronic kidney disease: translational opportunities and challenges

“…Observations in patients with kidney failure (Stage G5 CKD) associated circulating NPY levels with LVH [ 46 ] and incident cardiovascular complications [ 47 ] and the link between NPY and incident cardiovascular events was more recently confirmed in pre-dialysis CKD patients [ 48 ]. The direct link between NPY and left ventricular mass in kidney failure goes along with experimental observations showing that long-term subcutaneous infusion of NPY induces cardiac hypertrophy and dysfunction in rats [ 49 ], an effect mediated via calcineurin signaling [ 50 ] and the microRNA-216b/FoxO4 signaling pathway [ 51 ]. On the other hand, other experimental data indicate that NPY co-released with norepinephrine mitigates the hypertrophic response of adult ventricular cardiomyocytes to norepinephrine [ 52 ].…”

FOXO4 alleviates hippocampal neuronal damage in epileptic mice via the miR‐138‐5p/ROCK2 axis

“…In addition, acute brain injuries would cause neuroinflammation and increase the risk of EP, and the activation of its mediators TNF-α, IL-1β, and IL-6 would promote the progression of EP (Terrone et al, 2020). Our Mounting studies illustrated that FOXO4 could regulate the expressions of multiple miRNAs, such as miR-6,785-5p, miR-328-3p, and miR-216b (Qin & Guo, 2020;Wang et al, 2021;Yu et al, 2019).…”

“…Mounting studies illustrated that FOXO4 could regulate the expressions of multiple miRNAs, such as miR‐6,785‐5p, miR‐328‐3p, and miR‐216b (Qin & Guo, 2020; Wang et al, 2021; Yu et al, 2019). Moreover, miRNAs could modulate the neurogenesis of the adult hippocampus and the protein levels of EP and are regarded as key biomarkers of EP (Henshall, 2014) (Ma, 2018).…”

Saxagliptin Cardiotoxicity in Chronic Heart Failure: The Role of DPP4 in the Regulation of Neuropeptide Tone

“…Substance P and neuropeptide Y are important substrates of DPP4 that can mediate various detrimental effects in cardiovascular diseases [ 41 , 42 , 43 ]. Therefore, here we performed Western blot, ELISA, and radioimmunoassay experiments in order to measure the expression of DPP4, NPY, and SP at the protein level in interventricular septum samples from failing human hearts (patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM)) and also from healthy control (CON) hearts (detailed patients’ characteristics in Supplementary Tables S1 and S2 ).…”