# Novel Mechanisms of Cardiac pH Regulation During Ischemia/Reperfusion

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $29,090

## Abstract

Abstract:
 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.

## Key facts

- **NIH application ID:** 9999288
- **Project number:** 5F32HL149288-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Phung Nhat Thai
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,090
- **Award type:** 5
- **Project period:** 2019-08-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999288

## Citation

> US National Institutes of Health, RePORTER application 9999288, Novel Mechanisms of Cardiac pH Regulation During Ischemia/Reperfusion (5F32HL149288-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999288. Licensed CC0.

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