Increased thermogenesis in hairless SHR is associated with enhanced myocardial connexin-43 signaling and suppression of pro-fibrotic signaling

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic VEGA 2/0158/19, 2/0002/20 and Slovak Research and Development Agency APVV 18-0548,19-0317 Background We have previously shown that downregulation of myocardial gap junction channel protein, connexin-43 (Cx43), and up-regulation of extracellular matrix (ECM) proteins in spontaneously hypertensive rats (SHR) hearts promote occurrence of lethal arrhythmia. Cold acclimation has a potential for reducing cardiovascular risk but there is a gap of knowledge concern the heart response to adaptive thermogenesis. Purpose To explore myocardial Cx43 and ECM proteins in genetically hairless strain of SHR, that represents rewarding model of increased adaptive thermogenesis. Methods Adult hairless males and females SHRM strain that harbors mutated desmoglein-4 gene and their wild type SHR were housed at standard 22 °C (that is below thermo-neutrality for these animals) and 12:12 hour light: dark cycle. WKY control rats were used as reference normotensive strain. Heart samples of the left ventricular tissue from euthanatized rats were used for the proteomics of Cx43, protein kinases, which phosphorylates Cx43, and for ECM markers TGF-β, SMAD2/3, MMP-2, collagen-1. Immunofluoresence detection of Cx43 was performed to examine its myocardial topology. Key Results Cx43 protein and its phosphorylatetd status was reduced in males and females SHR vs WKY rat hearts. In contrast, adaptive thermogenesis resulted in increased both parameters in SHRM regardless the sex. Moreover, pathological topology of Cx43 attributed to its enhanced localization at lateral sides of the cardiomyocytes in SHR was attenuated in SHRM. In addition, there were gentle differences in protein levels of PKA, PKG, PKCε, MAPK, Akt between SHR and SHRM. Protein level of TGF-β and SMAD2/3 were increased in SHR vs WKY rat hearts but decreased in SHRM unlike collagen-1 that was not altered in SHRM vs SHR. Conclusion Findings revealed beneficial up-regulation of myocardial Cx43 along with down-regulation of extracellular matrix proteins in response of hairless SHR to increased thermogenesis.