Adaptation to exercise-induced stress is not dependent on cardiomyocyte α1A-adrenergic receptors. (June 2021)

• Record Type: Journal Article
• Authors: Kaidonis, Xenia; Niu, Wenxing; Chan, Andrea Y.; Kesteven, Scott; Wu, Jianxin; Iismaa, Siiri E.; Vatner, Stephen; Feneley, Michael; Graham, Robert M.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 155(2021)
• Page Start: 78
• Page End: 87
• Publication Date: 2021-06
• Subjects: sympathetic nervous system (SNS) -- adrenergic receptor (AR) -- transverse aortic constriction (TAC) -- MerCreMer (MCM) -- aortic systolic pressure (AoPs) -- aortic diastolic pressure (AoPd) -- mean arterial pressure (MAP) -- left ventricle (LV) -- right ventricle (RV) -- left ventricular systolic pressure (LVSP) -- end-diastolic pressure (EDP) -- wall thickness (h) -- chamber radius (r) -- wall thickness/chamber radius ratio (h/r) -- end-diastolic volume (EDV) -- end-systolic volume (ESV) -- stroke volume (SV) -- ejection fraction (EF) -- cardiac output (CO) -- stroke work (SW) -- single beat preload recruitable stroke work (SB PRSW) -- tibia length (TL) -- standard deviation (SD) -- honestly significant difference (HSD) -- transgenic (Tg) -- phosphofructokinase (PFK); α1A-adrenergic receptor -- Exercise -- Cardiac hypertrophy; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.02.010
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: The 'fight or flight' response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the β1 -adrenergic receptor subtype. However, the role of the α1A -adrenergic receptor, which has been suggested to be protective in cardiac pathology, has not been investigated in the setting of physiological stress. To explore this, we developed a tamoxifen-inducible, cardiomyocyte-specific α1A -adrenergic receptor knock-down mouse model, challenged mice to four weeks of endurance swim training and assessed cardiac outcomes. With 4-OH tamoxifen treatment, expression of the α1A -adrenergic receptor was knocked down by 80–89%, without any compensatory changes in the expression of other adrenergic receptors, or changes to baseline cardiac structure and function. Swim training caused eccentric hypertrophy, regardless of genotype, demonstrated by an increase in heart weight/tibia length ratio (30% and 22% in vehicle- and tamoxifen-treated animals, respectively) and an increase in left ventricular end diastolic volume (30% and 24% in vehicle- and tamoxifen-treated animals, respectively) without any change in the wall thickness/chamber radius ratio. Consistent with physiological hypertrophy, there was no increase in fetal gene program ( Myh7, Nppa, Nppb or Acta1 ) expression. In response to exercise-induced volume overload, stroke volume (39% and 30% in vehicle- and tamoxifen-treated animals, respectively), cardiac output/tibia length ratio (41% in vehicle-treated animals) and stroke work (61% and 33% in vehicle- and tamoxifen-treated animals, respectively) increased, regardless of genotype. These findings demonstrate that cardiomyocyte α1A -adrenergic receptors are not necessary for cardiac adaptation to endurance exercise stress and their acute ablation is not deleterious. Graphical abstract: Unlabelled Image Highlights: α1A -adrenergic receptor conditional knock-down mice have >80% Adra1a knock-down. α1A -adrenergic receptor conditional knock-down mice have no baseline deficits. Exercise induces eccentric cardiac hypertrophy in both knock-down and control mice. Both knock-down and control mice have improved cardiac function after exercise. Cardiac α1A -adrenergic receptors do not impact adaptation to endurance exercise.