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Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis.

ABSTRACT: Atrial dysfunction is highly prevalent and associated with increased severity of heart failure. While rapid excitation-contraction coupling depends on axial junctions in atrial myocytes, the molecular basis of atrial loss of function remains unclear. We identified approximately 5-fold lower junctophilin-2 levels in atrial compared with ventricular tissue in mouse and human hearts. In atrial myocytes, this resulted in subcellular expression of large junctophilin-2 clusters at axial junctions, together with highly phosphorylated ryanodine receptor (RyR2) channels. To investigate the contribution of junctophilin-2 to atrial pathology in adult hearts, we developed a cardiomyocyte-selective junctophilin-2-knockdown model with 0 mortality. Junctophilin-2 knockdown in mice disrupted atrial RyR2 clustering and contractility without hypertrophy or interstitial fibrosis. In contrast, aortic pressure overload resulted in left atrial hypertrophy with decreased junctophilin-2 and RyR2 expression, disrupted axial junctions, and atrial fibrosis. Whereas pressure overload accrued atrial dysfunction and heart failure with 40% mortality, additional junctophilin-2 knockdown greatly exacerbated atrial dysfunction with 100% mortality. Strikingly, transgenic junctophilin-2 overexpression restored atrial contractility and survival through de novo biogenesis of polyadic junctional membrane complexes maintained after pressure overload. Our data show a central role of junctophilin-2 cluster disruption in atrial hypertrophy and identify transgenic augmentation of junctophilin-2 as a disease-mitigating rationale to improve atrial dysfunction and prevent heart failure deterioration.

SUBMITTER: Brandenburg S

PROVIDER: S-EPMC6629097 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Postoperative acute renal failure in patients with obstructive jaundice is still a serious clinically complication, yet the mechanisms remain unclear. Renin-angiotensin-aldosterone system (RAAS) plays a central role in renal disease progression. Several lines of evidence shows that angiotensin-converting-enzyme-2 (ACE2), a main effector of RAAS acts as a local regulator for renal protection. This study aims to investigate the role of ACE2 and the effect of spironolactone treatment in obstructive jaundice(OJ) rats with renal injury. The rats with obstructive jaundice were established by bile duct ligation. Total bilirubin (TBil), serum creatinine (Scr) and the expression of ACE2 in kidney tissue of obstructive jaundice rats were detected. Comparatively, the expression of ACE2, renin, angiotensin II (AngII), angiotensin-(1-7)[Ang-(1-7)], aldosterone and intercellular adhesion molecule 1 (ICAM-1) in kidney tissues after spironolactone administration were measured by ELISA. Renal necrosis, inflammation and fibrosis induced by OJ were also measured by HE staining and Masson staining. The correlation between the expression of ACE2 and TBil, also the Scr level were investigated. With the time of common bile duct ligation prolonged, the TBil and Scr concentration increased while the expression of ACE2 in OJ rats' kidney tissues decreased. However, after spironolactone intervention, the expressions of ACE2, renin, AngII, Ang-(1-7), aldosterone and ICAM-1 in kidney tissue were changed, moreover, necrotic, inflammatory and fibrotic condition was also decreased. The relationship between the mRNA expression of ACE2 and TBil/Scr was observed to be moderately negatively correlated (r?=?-0.516, R2?=?0.292, P?<?0.01), (r?=?-0.576, R2?=?0.332, P?<?0.01), respectively. RAAS exerted an important effect in the renal damage caused by OJ. Spironolactone intervention not only improved the degree of renal fibrosis induced by OJ, but also upregulated the ACE2 expression in the kidney of OJ rats and rescued the renal function.

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Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis.

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