Ablation of Slc26a6 Mitigates Myocardial Ischemia/Reperfusion Injury
Year: 2025
Type: article
Abstract: Background/Objectives: Ischemic heart disease remains a leading cause of morbidity and mortality worldwide, accompanied by a major decline in local myocardial pH. However, the mechanisms of pH regulation and the homeostasis of H+ neutralizing buffers, such as HCO3−, in cardiomyocytes remain incompletely understood. We identified a solute carrier, Slc26a6, in mouse and human hearts playing key roles in the regulation of cardiac pH, excitability, and contractility. Slc26a6 is an acid loader, so we hypothesized that ablation of Slc26a6 may protect the heart from ischemia/reperfusion (I/R) injury. Methods: The I/R model was generated using wild type (WT) and Slc26a6 knockout (Slc26a6−/−) mice. Multidisciplinary in vivo, in vitro, and ex vivo approaches were used, including echocardiography, electrophysiology, hemodynamic monitoring, fluorescence microscopy, histochemistry, and cellular Ca2+ transients, sarcoplasmic reticulum Ca2+ load, and sarcomere shortening were recorded. Results: Troponin I level was lower in Slc26a6−/− I/R mice. Slc26a6−/− mice showed better systolic and diastolic function, reduced collagen deposition, and reduced infarct size compared to that of WT mice. Cellular experiments in measurement of sarcomere shortening, Ca2+ transients, and sarcoplasmic reticulum Ca2+ load in cardiomyocytes from the infarct zone supported the in vivo findings, demonstrating better single cell function in Slc26a6−/− compared to WT mice. Ex vivo pHi measurement showed elevated pHi in Slc26a6−/− mouse heart. Conclusions: Ablation of Slc26a6 protects the heart from I/R injury, suggesting the importance of Cl−/HCO3− exchange in cardiac pH regulation and I/R injury. The elevated pHi in Slc26a6−/− mouse heart may counterbalance the effects of the myocardium acidosis resulting from ischemia.
Source: Biomedicines
Authors: Phung N. Thai, Lu Ren, Daphne A. Diloretto, Pauline Trinh, Valeriy Timofeyev, Ning Zong, Richard Q. Ngo, Nipavan Chiamvimonvat, Xiao-Dong Zhang
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,137
Awards: Mechanistic underpinnings of psychosocial stressors on cardiovascular central control and cardiac arrhythmias, G2089753221, G5426395739, Psychosocial stRessors and Exposomics on CV health In underServed multiEthnic populations in Northern CA (PRECISE), G6947823565, Functional Regulation of Cardiac Chloride Homeostasis, Mechanistic links between inflammatory cascades and psychosocial stressors in CVD, Mechanisms Underpinning Afterload-Induced Atrial Fibrillation, Translational Study of Cardiac Dysfunction, G9000022628, G9000066181, G9000121000, G9000138392, G9000192339, G9000201784, G9000204046, G9000204613, G9000208910, G9000247267, G9000295784, G9000320539, Initiative for Maximizing Student Development at the University of California, Davis.
OpenAlex ID: W4416666802