Andelova Katarina, Sykora Matus, Farkasova Veronika, Stankovicova Tatiana, Szeiffova Bacova Barbara, Knezl Vladimir, Benova Tamara Egan, Pravenec Michal, Tribulova Narcis
Centre of Experimental Medicine, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, 832 32 Bratislava, Slovakia.
Biomolecules. 2024 Nov 26;14(12):1509. doi: 10.3390/biom14121509.
Due to poor treatment adherence and lifestyle-based interventions, chronic hypertension is a dominant risk factor predisposing individuals to heart failure and malignant arrhythmias. We investigated the impact of the postnatal acclimation of hairless SHR to ambient temperature that is, for them, below thermoneutrality, on the electrical coupling protein connexin-43 (Cx43) and pro-fibrotic markers in both heart ventricles of male and female hairless SHR rats compared to the wild SHR.
Some 6-month-acclimated male and female hairless SHR as well as age- and sex-matched wild SHR were included and compared with the non-hypertensive Wistar strain. The left and right heart ventricles were examined for Cx43 topology, myocardial structure, and the histochemistry of capillaries. The protein levels of Cx43, relevant protein kinases, and extracellular matrix proteins (ECMs) were determined by immunoblotting. MMP-2 activity was assessed via zymography, and susceptibility to malignant arrhythmias was tested ex vivo.
Cx43 and its phosphorylated variant pCx43 were significantly reduced in the left heart ventricles of wild SHR males, while to a lesser extent in the hairless SHR. In contrast, these proteins were not significantly altered in the right heart ventricles of males or in both heart ventricles in females, regardless of the rat strain. Pro-arrhythmic Cx43 topology was detected in the left heart ventricle of wild SHR and to a lesser extent in hairless SHR males. TGFβ protein was significantly increased only in the left ventricle of the wild SHR males. MMP-2 activity was increased in the right ventricle but not in the left ventricles of both males and females, regardless of the rat strain.
The findings indicate that the postnatal acclimation of hairless SHR to ambient temperature hampers the downregulation of Cx43 in the left heart ventricle compared to wild SHR males. The decline of Cx43 was much less pronounced in females and not observed in the right heart ventricles, regardless of the rat strain. It may impact the susceptibility of the heart to malignant arrhythmias.
由于治疗依从性差和基于生活方式的干预措施不足，慢性高血压是导致个体易患心力衰竭和恶性心律失常的主要危险因素。我们研究了无毛自发性高血压大鼠（SHR）在出生后适应低于其热中性温度的环境温度后，与野生型SHR相比，其心脏左右心室中电耦合蛋白连接蛋白43（Cx43）和促纤维化标志物的变化情况。
纳入6个月龄的雄性和雌性无毛SHR以及年龄和性别匹配的野生型SHR，并与非高血压的Wistar品系进行比较。对心脏左右心室进行Cx43拓扑结构、心肌结构和毛细血管组织化学检查。通过免疫印迹法测定Cx43、相关蛋白激酶和细胞外基质蛋白（ECM）的蛋白水平。通过酶谱法评估基质金属蛋白酶-2（MMP-2）活性，并在体外测试恶性心律失常的易感性。
野生型SHR雄性大鼠左心室中Cx43及其磷酸化变体pCx43显著降低，而在无毛SHR中降低程度较小。相比之下，无论大鼠品系如何，雄性大鼠右心室或雌性大鼠的两个心室中这些蛋白均无显著变化。在野生型SHR的左心室中检测到促心律失常的Cx43拓扑结构，在无毛SHR雄性大鼠中程度较轻。仅在野生型SHR雄性大鼠的左心室中，转化生长因子β（TGFβ）蛋白显著增加。无论大鼠品系如何，MMP-2活性在右心室中增加，但在雄性和雌性大鼠的左心室中均未增加。
研究结果表明，与野生型SHR雄性大鼠相比，无毛SHR出生后适应环境温度会阻碍左心室中Cx43的下调。无论大鼠品系如何，Cx43的下降在雌性大鼠中不太明显，在右心室中未观察到。这可能会影响心脏对恶性心律失常的易感性。
