Journal Article

Calcium Handling Remodeling Underlies Impaired Sympathetic Stress Response in Ventricular Myocardium from ICacna1c/I Haploinsufficient Rats

Decher, Niels, Walter, Kim, Schwa, Rohrbach, Susanne, Fender, Hauke, Kiper, Aytug K, Plačkić, Jelena, Kisko, Theresa M, Wöhr, Markus, Braun, Moria D, Kockskämper, Jens

2023

Overview

CACNA1C encodes the pore-forming α1C subunit of the L-type Ca[sup.2+] channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. Haploinsufficient Cacna1c+/− rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype is unknown. Here, we unraveled the cardiac phenotype of Cacna1c+/− rats with a main focus on cellular Ca[sup.2+] handling mechanisms. Under basal conditions, isolated ventricular Cacna1c+/− myocytes exhibited unaltered L-type Ca[sup.2+] current, Ca[sup.2+] transients (CaTs), sarcoplasmic reticulum (SR) Ca[sup.2+] load, fractional release, and sarcomere shortenings. However, immunoblotting of left ventricular (LV) tissue revealed reduced expression of Cav1.2, increased expression of SERCA2a and NCX, and augmented phosphorylation of RyR2 (at S2808) in Cacna1c+/− rats. The β-adrenergic agonist isoprenaline increased amplitude and accelerated decay of CaTs and sarcomere shortenings in both Cacna1c+/− and WT myocytes. However, the isoprenaline effect on CaT amplitude and fractional shortening (but not CaT decay) was impaired in Cacna1c+/− myocytes exhibiting both reduced potency and efficacy. Moreover, sarcolemmal Ca[sup.2+] influx and fractional SR Ca[sup.2+] release after treatment with isoprenaline were smaller in Cacna1c+/− than in WT myocytes. In Langendorff-perfused hearts, the isoprenaline-induced increase in RyR2 phosphorylation at S2808 and S2814 was attenuated in Cacna1c+/− compared to WT hearts. Despite unaltered CaTs and sarcomere shortenings, Cacna1c+/− myocytes display remodeling of Ca[sup.2+] handling proteins under basal conditions. Mimicking sympathetic stress with isoprenaline unmasks an impaired ability to stimulate Ca[sup.2+] influx, SR Ca[sup.2+] release, and CaTs caused, in part, by reduced phosphorylation reserve of RyR2 in Cacna1c+/− cardiomyocytes.

• Publisher: MDPI AG
• Subject: Resveratrol