High hydrostatic pressure induces atrial electrical remodeling through angiotensin upregulation mediating FAK/Src pathway activation. (March 2020)

• Record Type: Journal Article
• Authors: Li, Xin; Deng, Chun-Yu; Xue, Yu-Mei; Yang, Hui; Wei, Wei; Liu, Fang-Zhou; Guo, Hui-Ming; Liu, Yang; Wang, Zhao-Yu; Zhang, Meng-Zhen; Wu, Shu-Lin; Rao, Fang
• Is Part Of: Journal of molecular and cellular cardiology. Volume 140(2020)
• Page Start: 10
• Page End: 21
• Publication Date: 2020-03
• Subjects: Atrial fibrillation -- High hydrostatic pressure -- Electrical remodeling -- Angiotensin -- Src kinase -- Focal adhesion kinase; ACE-1 angiotensin-converting enzyme 1 -- AERP atrial effective refractory period -- AF atrial fibrillation -- Ang II angiotensin II -- Ang1–7 angiotensin 1–7 -- ANOVA one-way analysis of variance -- APD action potential duration -- AT1R angiotensin II - angiotensin type 1 receptor -- AVR aortic valve replacement -- BCL basic cycle lengths -- BP blood pressure -- BW body weight -- Cm membrane capacitance -- CSNRT rate-corrected sinus node recovery time -- DBP diastolic blood pressure -- ECG electrocardiogram -- EF ejection fraction -- EPS electrophysiologic study -- FAK focal adhesion kinase -- HW heart weight -- HR heart rate -- ICa, L L-type calcium current -- IKur ultra-rapid delayed rectifier potassium current -- Ito transient outward potassium current -- LA left atrial -- LAAs left atrial appendages -- LAD left atria diameter -- LCC L-type calcium channel -- MAP mean arterial pressure -- MVR mitral valve replacement -- PWD P-wave duration -- RA right atrium -- RAS renin-angiotensin system -- RMP resting membrane potential -- SBP systolic blood pressure -- SCL sinus cycle length -- SHR spontaneously hypertensive rat -- SNRT sinus node recovery time -- SR sinus rhythm -- TL tibial length; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.01.012
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Hypertension is an independent risk factor for atrial fibrillation (AF), although its specific mechanisms remain unclear. Previous research has been focused on cyclic stretch, ignoring the role of high hydrostatic pressure. The present study aimed to explore the effect of high hydrostatic pressure stimulation on electrical remodeling in atrial myocytes and its potential signaling pathways. Experiments were performed on left atrial appendages from patients with chronic AF or sinus rhythm, spontaneously hypertensive rats (SHRs) treated with or without valsartan (10 mg/kg/day) and HL-1 cells were exposed to high hydrostatic pressure using a self-developed device. Whole-cell patch-clamp recordings and western blots demonstrated that the amplitudes of ICa, L, Ito, and IKur were reduced in AF patients with corresponding changes in protein expression. Angiotensin protein levels increased and Ang1–7 decreased, while focal adhesion kinase (FAK) and Src kinase were enhanced in atrial tissue from AF patients and SHRs. After rapid atrial pacing, AF inducibility in SHR was significantly higher, accompanied by a decrease in ICa, L, upregulation of Ito and IKur, and a shortened action potential duration. Angiotensin upregulation and FAK/Src activation in SHR were inhibited by angiotensin type 1 receptor inhibitor valsartan, thus, preventing electrical remodeling and reducing AF susceptibility. These results were verified in HL-1 cells treated with high hydrostatic pressure, and demonstrated that electrical remodeling regulated by the FAK-Src pathway could be modulated by valsartan. The present study indicated that high hydrostatic pressure stimulation increases AF susceptibility by activating the renin-angiotensin system and FAK-Src pathway in atrial myocytes. Graphical abstract: Unlabelled Image Highlights: To explore the direct effects of hydrostatic pressure on the pathogenesis of AF. High-pressure increased AF susceptibility by altering ICa, L, Ito, IKur and APD. Ang II-AT1R was involved in high-pressure induced atrial electrical remodeling. FAK-Src was the potential signaling pathway and regulated by Ang II-AT1R.