Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats.

AIM: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. METHODS: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. RESULTS: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. CONCLUSION: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.

High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy.

Mitochondrial dysfunction and impaired Ca2+ handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca2+ release-activated calcium channel protein 1) calcium channel is important for the increase in Ca2+ entry into cardiomyocytes. We aimed to explore the mechanism of Drp1 and Orai1 in cardiomyocyte hypertrophy caused by high glucose (HG). We found that Zucker diabetic fat rats induced by administration of a high-fat diet develop cardiac hypertrophy and impaired cardiac function, accompanied by the activation of mitochondrial dynamics and calcium handling pathway-related proteins. Moreover, HG induces cardiomyocyte hypertrophy, accompanied by abnormal mitochondrial morphology and function, and increased Orai1-mediated Ca2+ influx. Mechanistically, the Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) prevents cardiomyocyte hypertrophy induced by HG by reducing phosphorylation of Drp1 at serine 616 (S616) and increasing phosphorylation at S637. Inhibition of Orai1 with single guide RNA (sgOrai1) or an inhibitor (BTP2) not only suppressed Drp1 activity and calmodulin-binding catalytic subunit A (CnA) and phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) expression but also alleviated mitochondrial dysfunction and cardiomyocyte hypertrophy caused by HG. In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca2+ entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1-Drp1 axis is a novel target for treating DCM.