Catestatin (CST), which is emerging as a novel cardiac modulator, can protect the heart against excessive sympathetic drive in hypertensive cardiomyopathy. The aim of this study is to investigate whether exogenous CST decreases excessive cardiac sympathetic drive and improves autonomic function and exerts cardioprotective effects in myocardial infarction (MI) rats. Rats were divided into a sham group, MI group, and MI plus CST (MI + CST) group. Four weeks later, the autonomic function of the animals was assessed by analyzing heart rate variability (HRV) and measuring plasma catecholamine. Cardiac function was evaluated via echocardiography. Electrophysiological characteristics were assessed in Langendorff-perfused hearts. Compared to the MI group, the chronic administration of CST significantly increased the standard deviation of normal-normal intervals (P < .01) and low-frequency (LF) and high-frequency (HF) HRV and decreased the ratio of LF-HF HRV (P < .01 for all). Additionally, the level of plasma catecholamine was reduced in the MI + CST group compared to the MI group (P < .01). Treatment with CST significantly increased ejection fraction (EF) and fraction shorting (FS) and significantly decreased the left ventricular end-systolic diameter and left ventricular end-diastolic diameter at 28 days postmyocardial infraction (P < .05 for all). After MI, the ventricular repolarization duration, such as QTc intervals and action potential duration (APD) at 90% repolarization, was prolonged, and this prolongation could be decreased by CST (P < .05 for all). The CST also increased the threshold of ADP alternans (P < .01). Moreover, ventricular arrhythmias were induced in 83% of the MI group but only 33% of the MI + CST group (P < .05). These results suggested that the chronic administration of CST plays a role in cardioprotection in MI rats, which may function by decreasing the cardiac sympathetic drive and improving autonomic function.

Previous studies demonstrated that Bailcalin (BAI) prevented cardiac injuries under different disease models. Whether BAI protected against type 2 diabetes mellitus- (T2DM-) associated cardiomyopathy was investigated in this study. T2DM was established by the combination of streptozotocin injection and high-fat diet in mice. BAI was administered daily for 6 months. After evaluating cardiac functions, mice hearts were removed and processed for morphological, biochemical, and molecular mechanism analyses. Neonatal rat cardiomyocytes (NRCM) were isolated and treated with high glucose and palmitate (HG/Pal) for in vitro investigation. BAI significantly ameliorated T2DM-induced cardiomyocyte hypertrophy, interstitial fibrosis, and lipid accumulation accompanied by markedly improved cardiac functions in diabetic mice. Mechanically, BAI restored decreased phosphorylation of AMPK and enhanced expression and nuclei translocation of Nrf2. In in vitro experiments, BAI also prevented NRCM from HG/Pal-induced apoptosis and oxidative stress injuries by increasing p-AMPK and Nrf2 accumulation. The means by which BAI restored p-AMPK seemed to be related to the antioxidative effects of Nrf2 after silencing AMPK or Nrf2 in NRCM. Furthermore, BAI regulated Nrf2 by inhibiting Nrf2 ubiquitination and consequent degradation mediated by Keap1. This study showed that BAI alleviated diabetes-associated cardiac dysfunction and cardiomyocyte injuries in vivo and in vitro via Keap1/Nrf2/AMPK-mediated antioxidation and lipid-lowering effects. BAI might be a potential adjuvant drug for diabetes cardiomyopathy treatment.

Cathelicidin-related antimicrobial peptide (CRAMP), antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. In the pathology of diabetic cardiomyopathy, endothelial-to-mesenchymal transition (EndMT) results from hyperglycemia-induced endothelial injury, leading to cardiac fibrosis. This study aims to evaluate the effect of CRAMP on EndMT and cardiac fibrosis on diabetic mice heart. Mice were subjected to streptozotocin to induce diabetes. CRAMP was administered by intraperitoneal injection (1 or 8 mg/kg/d) for 4 weeks from 12 weeks till 16 weeks after final streptozotocin injection. Cardiac dysfunction was observed in diabetic mice. Only 8 mg/kg/d CRAMP treatment proved cardiac function. Increased EndMT and fibrosis level were also observed in diabetic mice heart. 8mg/kg CRAMP inhibited EndMT and fibrosis level in diabetic mice. Mouse heart endothelial cells (MHECs) were treated with CRAMP and exposed to high glucose. Hyperglycemia-induced EndMT in MHECs was also attenuated by CRAMP treatment. Activation of TGFβ/Smad signalling was increased in diabetic mice heart tissue and hyperglycemia stimulated MHECs, which was prevented following CRAMP treatment. Activation of AMPKa1/mTOR showed similar changes. AMPKa1 siRNA abrogated the effects of CRAMP in MHECs. TGFβ/Smad inhibitor LY2109761 and AMPKa agonist AIRCA mimic the effect of CRAMP. In summary, CRAMP can inhibit EndMT, cardiac fibrosis and protect against diabetic cardiomyopathy by regulating AMPKa1/TGFβ signalling.

The Glp-1 analog, liraglutide (Lir), has been shown to reduce infarct size and improve cardiac function after myocardial ischemia in rodents with or without diabetes. However, the effect of Lir on angiotensin II (AngII) and pressure overload induced cardiac hypertrophy in nondiabetic mice and the underlying mechanisms are unclear. The aim of this study was to investigate the effect of Lir on cardiac hypertrophy induced by AngII infusion and pressure overload and to explore its possible mechanism. Mice were subjected to AngII as well as thoracic aorta coarctation (TAC) to induce a cardiac hypertrophy model. Mice were daily injected with either liraglutide or saline for 2 weeks after AngII infusion. Mice were also subjected to either liraglutide or saline for 25 days after TAC surgery. Neonatal rat cardiomyocytes and human AC cell lines were stimulated with AngII to induce a cardiomyocytes hypertrophy model. The results indicated Lir significantly inhibited cardiac hypertrophy and fibrosis and improved cardiac function in both the AngII and pressure overload induced model. The in vitro study showed that Lir inhibits AngII induced cell hypertrophy. Mechanistically, Lir directly suppressing the activation of PI3K/Akt1 and stimulated AMPKα signaling pathways in cardiomyocytes, which was confirmed by use of an mTOR activator (MHY1485), overexpression of constitutively active Akt, and the knockdown of AMPKa2 expression. Moreover, the protective effects of Lir were lost in AMPKa2 knockout mice. Taken together, Lir inhibits AngII and pressure overload induced cardiac remodeling via regulating PI3K/Akt1 and AMPKα signaling.