Key result
Sorcin knockout reduces 3-week post-TAC survival by ~36 percentage points and worsens ventricular arrhythmias.
Why the study?
Does genetic ablation of sorcin predispose mice and ventricular cardiomyocytes to Ca2+ disturbances, delayed afterdepolarizations, ventricular arrhythmias, and mortality under acute β-adrenergic or chronic mechanical stress?
Does genetic ablation of sorcin predispose mice and ventricular cardiomyocytes to Ca2+ disturbances, delayed afterdepolarizations, ventricular arrhythmias, and mortality under acute β-adrenergic or chronic mechanical stress?
This preclinical study demonstrates that endogenous sorcin is critical for maintaining cardiac Ca2+ homeostasis during β-adrenergic stimulation, and its deficiency creates a CPVT-like arrhythmogenic substrate characterized by RyR2 hyperactivity, NCX/LTCC overexpression, DADs, and lethal ventricular arrhythmias.
Answers are grounded in this paper and cite their sources.
No immediate clinical implications for sorcin modulation; leaves open its role as a therapeutic target in human stress-induced arrhythmias.
Sorcin, a penta-EF hand Ca 2+ -binding protein expressed in cardiomyocytes, is known to interact with ryanodine receptors and other Ca 2+ regulatory proteins. To investigate sorcin's influence on cardiac excitation-contraction coupling and its role in the development of cardiac malfunctions, we generated a sorcin knockout (KO) mouse model. Sorcin KO mice presented ventricular arrhythmia and sudden death when challenged by acute stress induced by isoproterenol plus caffeine. Chronic stress, which was induced by transverse aortic constriction, significantly decreased the survival rate of sorcin KO mice. Under isoproterenol stimulation, spontaneous Ca 2+ release events were frequently observed in sorcin KO cardiomyocytes. Sorcin KO hearts of adult, but not young mice developed overexpression of L-type Ca 2+ channel and Na + -Ca 2+ exchanger, which enhanced I Ca and I NCX . Consequently, spontaneous Ca 2+ release events in sorcin KO cardiomyocytes were more likely to induce arrhythmogenic delayed afterdepolarizations. Our study demonstrates sorcin deficiency may trigger cardiac ventricular arrhythmias due to Ca 2+ disturbances, and evidences the critical role of sorcin in maintaining Ca 2+ homeostasis, especially during the adrenergic response of the heart.
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Chen et al. (2017) studied Sorcin deficiency and stress-induced ventricular arrhythmias (n=80). Sorcin gene (Sri) knockout plus acute β-adrenergic stimulation (isoproterenol or epinephrine/caffeine) or chronic pressure overload (transverse aortic constriction) vs. Wild-type (Sri+/+) littermate control mice was evaluated on 3-week survival rate following chronic stress induced by transverse aortic constriction (TAC) (p=<0.01). Sorcin knockout in mice significantly decreased 3-week survival after transverse aortic constriction compared to wild-type (52% vs 88%, p<0.01) and prolonged stress-induced ventricular arrhythmias.
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