Chantal J.M. van Opbergen PhD , Lilian K. Gutierrez PhD , Giorgia Bertoli PhD , Mingliang Zhang PhD , Sarah Boyce BSc , Yan Deng MD, PhD , Michael Cammer MFA, MAT , Feng-Xia Liang PhD , Mario Delmar MD, PhD
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引用次数: 0
Abstract
Background
Plakophilin-2 (PKP2) is a component of the desmosome. Pathogenic variants can lead to arrhythmogenic cardiomyopathy (PKP2-ACM). In patients with PKP2-ACM, exercise and catecholamine surges negatively impact arrhythmia incidence and severity.
Objective
The study aimed to characterize remodeling of the sympathetic input and adrenergic response in hearts of PKP2-deficient mice (PKP2cKO) subjected to endurance exercise.
Methods
We used expansion microscopy and structured illumination to characterize the abundance of beta 1-adrenergic receptors (β1-ARs) in the sarcolemma in PKP2cKO-myocytes, sedentary or trained, and Cre-negative controls. We prevented endogenous catecholamine import by short hairpin RNA (shRNA)-mediated knockdown of its transporter [organic cation transporter 3 (OCT3)] and characterized differential effects of isoproterenol (membrane permeable) vs norepinephrine (non-membrane permeable) on Ca2+ transient dynamics. Separately, we evaluated the distribution of sympathetic terminals in PKP2cKO-trained hearts vs controls.
Results
Exercise led to “increased” abundance of sarcolemma β1-ARs in control, and “decreased” abundance in PKP2cKO-myocytes. OCT3 knockdown drastically reduced the response of trained PKP2cKO-myocytes to norepinephrine but not isoproterenol, indicating preserved response to native catecholamines by intracellular (dyad-associated) receptors in the setting of a reduced sarcolemma pool. In tissue, we observed reduced abundance of sympathetic terminals and heterogeneous distribution across the myocardium.
Conclusion
Endurance exercise in PKP2-deficient myocytes leads to a reduced pool of functional β1-ARs in the sarcolemma and yet availability of intracellular receptors, which can activate selected (and heterogeneous) routes of intracellular signaling cascades. We speculate that remodeling of nerve terminals affects sympathetic input distribution and hence, regional modulation of excitability and conduction. These changes can facilitate cell-generated triggered activity and heterogeneity of the underlying substrate, setting the stage for life-threatening arrhythmias.
期刊介绍:
HeartRhythm, the official Journal of the Heart Rhythm Society and the Cardiac Electrophysiology Society, is a unique journal for fundamental discovery and clinical applicability.
HeartRhythm integrates the entire cardiac electrophysiology (EP) community from basic and clinical academic researchers, private practitioners, engineers, allied professionals, industry, and trainees, all of whom are vital and interdependent members of our EP community.
The Heart Rhythm Society is the international leader in science, education, and advocacy for cardiac arrhythmia professionals and patients, and the primary information resource on heart rhythm disorders. Its mission is to improve the care of patients by promoting research, education, and optimal health care policies and standards.