Cardiac Cx43 Signaling Is Enhanced and TGF-β1/SMAD2/3 Suppressed in Response to Cold Acclimation and Modulated by Thyroid Status in Hairless SHRM

Abstract

The hearts of spontaneously hypertensive rats (SHR) are prone to malignant arrhythmias, mainly due to disorders of electrical coupling protein Cx43 and the extracellular matrix. Cold acclimation may induce cardio-protection, but the underlying mechanisms remain to be elucidated. We aimed to explore whether the adaptation of 9-month-old hairless SHRM to cold impacts the fundamental cardiac pro-arrhythmia factors, as well as the response to the thyroid status. There were no significant differences in the registered biometric, redox and blood lipids parameters between hairless (SHRM) and wild type SHR. Prominent findings revealed that myocardial Cx43 and its variant phosphorylated at serine 368 were increased, while an abnormal cardiomyocyte Cx43 distribution was attenuated in hairless SHRM vs. wild type SHR males and females. Moreover, the level of β-catenin, ensuring mechanoelectrical coupling, was increased as well, while extracellular matrix collagen-1 and hydroxyproline were lower and the TGF-β1 and SMAD2/3 pathway was suppressed in hairless SHRM males compared to the wild type strain. Of interest, the extracellular matrix remodeling was less pronounced in females of both hypertensive strains. There were no apparent differences in response to the hypothyroid or hyperthyroid status between SHR strains concerning the examined markers. Our findings imply that hairless SHRM benefit from cold acclimation due to the attenuation of the hypertension-induced adverse downregulation of Cx43 and upregulation of extracellular matrix proteins.

Impact of volume overload on cardiac connexin-43 and extracellular matrix of normotensive and hypertensive Ren-2 transgenic rats: Effects of treatment with Trandolapril and Losartan

“…In this context it should be noted that we did not observe enhanced "lateralization" of Cx43 in hypertrophied cardiomyocytes of ACF-affected HSD rats. While such abnormal distribution of Cx43 was induced by pressure overload in TGR, likewise in other spontaneously hypertensive rat strain 17,18,34 . It suggests difference in Cx43 topology (lateralisation) between volume overload induced eccentric versus pressure overload induced concentric hypertrophy.…”

“…Likewise in HSD rats treated with trandolapril 30 . Moreover, treatment increased alkaline phosphatase activity in arterial part of capillary network in HSD as well as TGR that may contribute to improvement of heart function 34 .…”

Anti-Fibrotic Potential of Angiotensin (1-7) in Hemodynamically Overloaded Rat Heart

“…Microscopic images were captured by Zeiss Apotome 2 microscope (Carl Zeiss, Jena, Germany). Quantification of Cx43 immunofluorescence signal was performed on a 15 randomly selected myocardial area (per heart) and expressed as total integral optical density per area (IOD) [ 62 ].…”

The treatment with sGC stimulator improves survival of hypertensive rats with volume-overload induced heart failure and cardio-renal syndrome

“…According to Lojda (Lojda and Gutmann 1976) with modi cations (Andelova et al 2022), 10 µm thick left ventricular myocardial tissue cryosections were used for histological hematoxylin-eosin staining and enzyme histochemical demonstration of alkaline phosphatase (AP).…”

“…The intensity of staining corresponding to the activity of AP, was de ned as an area, with a number of pixels, with a code lower than 128 on the "0-255 RGB colour scale". The total number of positive pixels was expressed as a total integral optical density per area (IOD) (Image-Pro Plus) (Andelova et al 2022).…”