Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

Abstract

High plasma levels of homocysteine (Hcy) are regarded as a risk factor for atrial fibrillation (AF), which is closely associated with the pathological consequence of atrial fibrosis and can lead to heart failure with a high mortality rate; here, we show that atrial fibrosis is mediated by the relationship between canonical transient receptor potential 3 (TRPC3) channels and sirtuin type 1 (SIRT1) under the stimulation of Hcy. The left atrial appendage was obtained from patients with either sinus rhythm (SR) or AF and used to evaluate the relationship between the concentration of Hcy and a potential mechanism of cardiac fibrosis mediated by TRPC3 and SIRT1. We next performed transverse aortic constriction (TAC) in mouse to investigate the relationship. The mechanisms underlying atrial fibrosis involving TRPC3 and SIRT1 proteins were explored by co‐IP, BLI and lentivirus transfection experiments. qPCR and WB were performed to analyse gene and protein expression, respectively. The higher level of atrial fibrosis was observed in the HH mouse group with a high Hcy diet. Such results suggest that AF patients may be more susceptible to atrial fibrosis and possess a high probability of progressing to hyperhomocysteinemia. Moreover, our findings are consistent with the hypothesis that TRPC3 channel up‐regulation leads to abnormal accumulation of collagen, with the down‐regulation of SIRT1 as an aetiological factor of high Hcy, which in turn predisposes to atrial fibrosis and strongly enhances the possibility of AF.

TRPC Channels: Dysregulation and Ca2+ Mishandling in Ischemic Heart Disease

“…For instance, experiments performed in TRPC1/4 double-KO mice revealed significant amelioration of pressure overload-induced hypertrophy and interstitial fibrosis, which is explained by a reduced activity of TRPC1-and 4-dependent basal Ca 2+ entry in adult ventricular myocytes [65]. At the same time, TRPC3 knockdown, using a small hairpin RNA lentivirus through the tail vein of mice, efficiently suppresses the extent of atrial fibrosis induced by TAC [116].…”

Effect of inositol 1, 4, 5-trisphosphate receptor dependent Ca2+ release in atrial fibrillation

“…It is thought to be integral to inhomogeneous conduction contributing to re-entry. Previous experiments affirmed that structural remodeling in the atrium can be easily detected in patients with paroxysmal and permanent AF, [ 5 ] and the accumulation of collagen I was inhibited in an IP 3 R-deficient model. [ 6 ] It has further confirmed that IP 3 Rs mediate electrical remodeling that can facilitate atrial structural remodeling via enhanced afterload and peripheral resistance.…”

Genetic Complexity of Sinoatrial Node Dysfunction

“…TRPC3 is upregulated in AF patients and AF animal models ( Harada et al, 2012 ). Finally, TRPC-3 channel upregulation also has been shown to cause an increased accumulation of collagen consistent with atrial fibrosis in mice ( Han et al, 2020 ). FK506-binding protein 52 (FKBP52 or KBP4) has been identified as an interaction partner of TRPC3 and may be an important player in TRPC3-related therapy going forward.…”