Tur Jared, Chapalamadagu Kalyan C, Manickam Ravikumar, Cheng Feng, Tipparaju Srinivas M
Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
Metabolites. 2021 Mar 29;11(4):201. doi: 10.3390/metabo11040201.
Kvβ subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 plays a significant role in cardiovascular pathophysiology by modulating the cardiac excitability and gene responses. We utilized an isoproterenol-infused mouse model to investigate the role of Kvβ2 and the cardiac function, biochemical changes, and molecular responses. The deletion of Kvβ2 attenuated the QTc (corrected QT interval) prolongation at the electrocardiographic (ECG) level after a 14-day isoproterenol infusion, whereas the QTc was significantly prolonged in the littermate wildtype group. Monophasic action potentials verified the ECG changes, suggesting that cardiac changes and responses due to isoproterenol infusion are mediated similarly at both the in vivo and ex vivo levels. Moreover, the echocardiographic function showed no further decrease in the ejection fraction in the isoproterenol-stimulated Kvβ2 knockout (KO) group, whereas the wildtype mice showed significantly decreased function. These experiments revealed that Kvβ2 plays a significant role in cardiovascular pathophysiology. Furthermore, the present study revealed SLC41a3, a major solute carrier transporter affected with a significantly decreased expression in KO vs. wildtype hearts. The electrical function showed that the decreased expression of SLC41a3 in Kvβ2 KO hearts led to decreased Mg responses, whereas, in the wildtype hearts, Mg caused action potential duration (APD) shortening. Based on the in vivo, ex vivo, and molecular evaluations, we identified that the deletion of Kvβ2 altered the cardiac pathophysiology mediated by SLC41a3 and altered the NAD (nicotinamide adenine dinucleotide)-dependent gene responses.
Kvβ亚基属于醛糖酮还原酶超家族，该家族在离子通道调节中起重要作用并调节生理反应。然而，Kvβ2在心脏病理生理学中的作用尚未得到研究，因此，在本研究中，我们假设Kvβ2通过调节心脏兴奋性和基因反应在心血管病理生理学中起重要作用。我们利用异丙肾上腺素灌注小鼠模型来研究Kvβ2的作用以及心脏功能、生化变化和分子反应。在14天的异丙肾上腺素灌注后，Kvβ2的缺失在心电图（ECG）水平上减轻了QTc（校正QT间期）延长，而在同窝野生型组中QTc显著延长。单相动作电位证实了心电图变化，表明异丙肾上腺素灌注引起的心脏变化和反应在体内和体外水平上的介导方式相似。此外，超声心动图功能显示，在异丙肾上腺素刺激的Kvβ2基因敲除（KO）组中射血分数没有进一步降低，而野生型小鼠的功能显著降低。这些实验表明Kvβ2在心血管病理生理学中起重要作用。此外，本研究还发现了SLC41a3，这是一种主要的溶质载体转运蛋白，在KO心脏与野生型心脏中其表达显著降低。电生理功能显示，Kvβ2基因敲除心脏中SLC41a3表达的降低导致镁反应降低，而在野生型心脏中，镁导致动作电位时程（APD）缩短。基于体内、体外和分子评估，我们确定Kvβ2的缺失改变了由SLC41a3介导的心脏病理生理学，并改变了烟酰胺腺嘌呤二核苷酸（NAD）依赖性基因反应。
