Cardiovascular disease remains the leading cause of mortality compared to all cancers combined. Approximately 720,000 Americans will be diagnosed of coronary artery disease this year. Approximately half of these patients will be susceptible to acute myocardial infarction (MI), as well as complications that can lead to heart failure and sudden cardiac death. Therefore, it is critical to gain new insights into the molecular and cellular mechanisms to develop novel therapeutic paradigms to limit ischemia reperfusion injury. One of the hallmark features that occur during an MI is a decrease in intracellular pH (pHi). Under normal physiological conditions in the heart, pHi homeostasis is maintained by H+ and HCO3- transporters and buffering systems, which counter the pHi fluctuation on a beat-to-beat basis. In contrast, during hypoxic conditions when aerobic is switched to anaerobic respiration, there is an accumulation of lactic acid that can impair transporters and contribute to the decline in pHi. If the change in pHi is uncompensated, this can affect electrical excitability, intracellular Ca2+ homeostasis, ultimately impairing cardiac function. Indeed, a significant gap in our knowledge exists regarding how pH is regulated and compensated during and after an MI. To this end, our laboratory has recently identified the critical roles of a novel anion transport, Slc26a6, in pH regulation in cardiomyocytes. It was previously reported that Slc26a6 is the predominant Cl-/HCO3- exchanger in the heart based on the transcript levels. Since CO2/HCO3- is one of the primary pH buffering systems, transport of HCO3- across the plasma membrane will affect pHi. To our surprise, we discovered that both human and mouse Slc26a6?s activity is electrogenic, suggesting its crucial role not only in pH regulation but also in cardiac excitability. We demonstrate that ablation of this anion exchanger in a mouse model results in a significant increase in pHi in isolated cardiomyocytes, affirming its role in pHi regulation. However, the role of this transporter after MI, a pathological state where pHi dysregulation contributes to the pathogenesis, remains unknown. We hypothesize that since Slc26a6 is involved in pHi homeostasis and cardiac function, the protein plays a critical role after a myocardial infarction (MI). Specifically, since Slc26a6 serves as an acid loader by exchanging extracellular Cl- for intracellular HCO3-, inhibition of Slc26a6 during I/R maybe cardioprotective leading to a decrease in the I/R injury and adverse remodeling. Multidisciplinary techniques combined with state-of-the-art imaging will be used to test the hypothesis using in vivo, ex vivo and in vitro analyses. The completion of the study will uncover possible novel therapeutic targets that may be effectively translated into clinical setting.
Cardiovascular disease is the leading cause of mortality in United States and causes more deaths than all cancers combined. Although cardiac ischemia and acid-base regulation in cardiac myocytes is inexplicably tied to Cl- homeostasis in the heart, the mechanism remains incompletely understood. This proposal aims to reveal a missing molecular link between Cl- homeostasis and acid-base regulation in the heart. 1
