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Physiological Functions of Cl-/HCO3- Exchangers and Na+/ HCO3- Cotransporters in Heart

Vairamani, Kanimozhi
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439303119

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
The function of bicarbonate transporters has been extensively studied in epithelial tissues, but their function in heart is not well understood. Cardiac tissue expresses an abundance of bicarbonate transporters (Cl-/HCO3- exchangers and Na+/ HCO3- cotransporters) that are typically viewed as being involved in the regulation of intracellular pH (pHi). However, the high expression of bicarbonate transporters in heart and results of the current thesis research suggests that pHi regulation may not be their major function. Anion exchanger isoform 3 (AE3) is the most abundant Cl-/HCO3- exchanger in heart. Mice lacking AE3 have normal cardiac function, but loss of AE3 in a hypertrophic cardiomyopathy (HCM) model leads to heart failure and reduces survival. Moreover, AE3 KO mice have an impaired force-frequency response (FFR) when paced at higher heart rates in vivo. AE3 has been proposed to work in a coupled system with the Na+/H+ exchanger, with the resulting increase in Na+-loading leading to Ca2+-loading, which in turn contributes to cardiac hypertrophy. Studies have shown that AE3-null mice have reduced heart weight to body weight ratio, suggesting that AE3 may play such a role in hypertrophy. However, loss of AE3 does not reduce hypertrophy or impair cardiac function in response to pressure overload. To further understand the molecular mechanism of why loss of AE3 impaired cardiac function in the HCM model and impaired FFR during atrial pacing, RNA seq analysis of WT and AE3 KO hearts was performed to analyze differential gene expression patterns in great detail. Detailed analysis of RNA seq data suggested the occurrence of impaired O2/CO2 balance in AE3 KO cardiomyocytes. Genes encoding proteins involved in hypoxia responses, angiogenesis, vasodilation, glucose and fatty acid metabolism, cardiac conduction and electrical activity, and myofibrillar organization were differentially expressed in AE3 KO hearts. The pattern of changes support a model in which AE3-mediated Cl-/HCO3- exchange, in a coupled system likely involving parallel H+ and Cl- extrusion mechanisms, is responsible for efficient disposal of CO2. Most of the differential expression changes in AE3 KO hearts could be interpreted as adaptive changes that provide compensation for the loss of AE3-mediated HCO3- extrusion in heart. Other Cl-/HCO3- exchangers, AE2 and PAT1, were slightly upregulated and may provide partial compensation for the loss of AE3 in heart. Mice with cardiac specific knockdown of AE2, which is expressed at much lower levels than AE3, have normal cardiovascular performance and expression of major calcium handling proteins in heart, consistent with a supplementary role. The sodium dependent bicarbonate cotransporters (NBC) are HCO3- uptake mechanisms in heart. Of the two NBCs in heart, the electrogenic NBC (NBCe1) is expressed at higher levels than the electroneutral NBC (NBCn1). Previous studies have reported that inhibition of NBCe1 protects against ischemia reperfusion (I/R) injury. In order to understand the role of NBCe1 in heart, we generated a conditional cardiac-specific NBCe1 KO mouse. Though loss of NBCe1 did not affect cardiovascular function, NBCe1 KO mice had less apoptotic cell death in response to in vivo I/R suggesting that loss of NBCe1 may protect against I/R injury. The studies presented here suggest that bicarbonate transporters have important functions in heart. Though loss of AE3 did not reduce hypertrophy in response to pressure-overload, RNA seq analysis indicates that AE3 may be involved in efficient disposal of CO2 from the cardiomyocytes. These observations along with the previous studies from our lab, indicate that AE3 has an important function in heart and that inhibition of AE3 for the treatment of heart disease, as proposed by others, would not be an appropriate therapeutic strategy.
Gary Edward Shull, Ph.D. (Committee Chair)
Jerry Lingrel, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
David Wieczorek, Ph.D. (Committee Member)
Animals; Biology; Physiology

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Citations

  • Vairamani, K. (2015). Physiological Functions of Cl-/HCO3- Exchangers and Na+/ HCO3- Cotransporters in Heart [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439303119

    APA Style (7th edition)

  • Vairamani, Kanimozhi. Physiological Functions of Cl-/HCO3- Exchangers and Na+/ HCO3- Cotransporters in Heart. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439303119.

    MLA Style (8th edition)

  • Vairamani, Kanimozhi. "Physiological Functions of Cl-/HCO3- Exchangers and Na+/ HCO3- Cotransporters in Heart." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439303119

    Chicago Manual of Style (17th edition)

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