Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na^(+)-H^(+)exchanger-1 expression

The mammalian nuclear pore complex is comprised of∼30 different nucleoporins(Nups).It governs the nuclear import of gene expression modulators and the export of mRNAs.In cardiomyocytes,Na1-H1 exchanger-1(NHE1)is an integral membrane protein that exclusively regulates intracellular pH(pHi)by exchanging one intracellular H1 for one extracellular Na1.However,the role of Nups in cardiac NHE1 expression remains unknown.We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA.The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5′-UTR(2412 to2213 nt)of nhe1mRNA.Nup35 ablationweakensthe resistance of cardiomyocytes to an acid challenge by depressingNHE1 expression.Moreover,we identify thatNup35 andNHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro.Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification.We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression.This finding reveals a novel regulatory mechanism of cardiomyocyte pHi,and may provide insight into the therapeutic strategy for ischemic cardiac diseases.