Abstract
Hypertension is a major cardiovascular risk factor for atrial fibrillation (AF) worldwide. However, the role of mechanical stress caused by hypertension on downregulating the L-type calcium current (ICa,L), which is vital for AF occurrence, remains unclear. Therefore, the aim of the present study was to investigate the role of Piezo1, a mechanically activated ion channel, in the decrease of ICa,L in response to high hydrostatic pressure (HHP, one of the principal mechanical stresses) at 40 mmHg, and to elucidate the underlying pathways. Experiments were conducted using left atrial appendages from patients with AF, spontaneously hypertensive rats (SHRs) treated with valsartan (Val) at 30 mg/kg/day and atrium-derived HL-1 cells exposed to HHP. The protein expression levels of Piezo1, Calmodulin (CaM), and Src increased, while that of the L-type calcium channel a1c subunit protein (Cav1.2) decreased in the left atrial tissue of AF patients and SHRs. SHRs were more vulnerable to AF, with decreased ICa,L and shortened action potential duration, which were ameliorated by Val treatment. Validation of these results in HL-1 cells in the context of HHP also demonstrated that Piezo1 is required for the decrease of ICa,L by regulating Ca2+ transient and activating CaM/Src pathway to increase the expression of paired like homeodomain-2 (Pitx2) in atrial myocytes. Together, these data demonstrate that HHP stimulation increases AF susceptibility through Piezo1 activation, which is required for the decrease of ICa,L via. the CaM/Src/Pitx2 pathway in atrial myocytes.
Highlights
Atrial fibrillation (AF), one of the most frequent cardiac arrhythmias, is associated with increased risks of stroke and heart failure, and continues as a burden to healthcare systems worldwide [1]
Src were significantly greater in the Left atrial appendages (LAAs) of atrial fibrillation (AF) patients than the sinus rhythm (SR) controls (0.46 ± 0.10 vs. 1.32 ± 0.11, p < 0.01; 0.60 ± 0.12 vs. 1.13 ± 0.12, p < 0.01; 0.63 ± 0.12 vs. 1.11 ± 0.09, p < 0.01; for Piezo1, CaM and Src, respectively), while Cav1.2 protein levels were lower in the LAAs of AF patients than the SR controls (0.97 ± 0.08 vs. 0.57 ± 0.10, p < 0.01; Figure 1A)
These results indicate that Piezo1, CaM, and Src might participate in the decrease of atrial ICa,L in AF
Summary
Atrial fibrillation (AF), one of the most frequent cardiac arrhythmias, is associated with increased risks of stroke and heart failure, and continues as a burden to healthcare systems worldwide [1]. Available therapies include antiarrhythmic drugs and catheter ablation. A better understanding of the mechanisms underlying substrate formation may provide promising and novel insights into the treatment of AF. Hypertension is a common risk factor for AF. As a modifiable risk factor, management of high blood pressure (BP) can reduce the risks of new-onset AF and recurrence after cardioversion or ablation [3, 4]. Previous studies have revealed that mechanical stress can lead to electrical remodeling of AF [5–8], which is characterized by a decrease in L-type calcium current (ICa,L) and shortening of the action potential duration (APD) [9, 10]. The specific molecular mechanisms underlying the perception and translation of mechanical stress into a cellular response in atrial myocytes remains unclear
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