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Abstract
C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, which exerts protective function in ischemic or diabetic heart injury. However, the role of CTRP3 in cardiac hypertrophy remains unclear. The aim of this study was to investigate the pharmacological effects of CTRP3 on pathological cardiac hypertrophy induced by hypertension. Male C57BL/6 J wild-type (WT) mice, Ctrp3 knockout mice, and mice infected with lentivirus overexpressing mouse Ctrp3 underwent sham surgery or transverse aortic constriction (TAC) surgery. After 4 weeks, cardiac hypertrophy, fibrosis, and cardiac function were examined. Compared with WT mice, Ctrp3 deficiency substantially impaired contractile dysfunction, exacerbated the enlargement of cardiomyocytes and myocardial fibrosis, and reprogramed the expression of pathological genes after TAC. Conversely, CTRP3 overexpression played a role in restoring the left ventricular cardiac contractile function, alleviating cardiac hypertrophy and fibrosis, and inhibiting the expression of hypertrophic and fibrotic signaling in mice after TAC. Furthermore, CTRP3 regulated the expression of the p38/CREB pathway and of the primary modulating factors of the endoplasmic reticulum stress, i.e., GRP78 and the downstream molecules eukaryotic translation inhibition factor 2 submit α, C/EBP homologous protein, and inositol-requiring enzyme-1. Further, inhibition of p38 MAPK by SB203580 blunted the ER stress intensified by Ctrp3 deficiency. In vitro, CTRP3 protected neonatal rat cardiac myocytes against phenylephrine-induced cardiomyocyte hypertrophy. We conclude that CTRP3 protects the host against pathological cardiac remodeling and left ventricular dysfunction induced by pressure overload largely by inhibiting the p38/CREB pathway and alleviating p38-induced ER stress.
Highlights
Continuous hypertrophic stimulus such as pressure overload, ischemia, inflammation, and oxidative stress gradually converts the compensatory response into an Regardless of the continuously developing diagnosis and therapeutic approaches, heart failure has still a poor outcome with nearly 25–50% mortality rate in 5 yearsOfficial journal of the Cell Death Differentiation AssociationZhang et al Cell Death and Disease (2019)10:520 after diagnosis[6]
We conclude that C1q-tumor necrosis factor-related protein-3 (CTRP3) protects the host against pathological cardiac remodeling and left ventricular dysfunction induced by pressure overload largely by inhibiting the p38/cAMP response elementbinding protein (CREB) pathway and alleviating p38-induced endoplasmic reticulum (ER) stress
After 2 and 4 weeks of transverse aortic constriction (TAC), CTRP3 protein expression level was significantly increased with time after TAC, in parallel with increased levels of the hypertrophic indices including atrial natriuretic peptide (ANP) and myosin heavy chain β (β-MHC) (Fig. S1a)
Summary
Zhang et al Cell Death and Disease (2019)10:520 after diagnosis[6]. Seeking out novel effective therapeutic targets to prevent and alleviate the pathological cardiac hypertrophy is urgent and necessary. The mitogen-activated protein kinase (MAPK) pathway is closely involved in cardiac hypertrophy[7,8]. MAPKs are major regulatory kinases that directly control numerous physiological processes, including cell proliferation, cell growth, and stress responses. Protein 38 MAPK (p38), one branch of MAPKs, can be activated and phosphorylated under pressure-load stimulation[9]. Numerous groups have studied the role of p38 MAPK in various cardiac hypertrophy settings and showed that pathological cardiac hypertrophy can be suppressed by inhibiting the phosphorylation of p388,10–12. Various forms of pathological cardiac hypertrophy can be attenuated by inhibiting the phosphorylation of CREB16,17
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