NHE-1 inhibition improves cardiac mitochondrial function through regulation of mitochondrial biogenesis during postinfarction remodeling.
We have recently demonstrated that mitochondrial respiratory dysfunction and mitochondrial permeability transition pore opening during postinfarction remodeling are prevented by the Na(+)/H(+) exchange-1 (NHE-1)-specific inhibitor EMD-87580 (EMD). One of the mechanisms underlying the beneficial effect of NHE-1 inhibition on mitochondria could result from the drug's ability to regulate transcriptional factors responsible for mitochondrial function. In the present study, the effect of EMD on the expression of nuclear factors involved in mitochondrial biogenesis and expression of nuclear (COXNUCSUB IV) and mitochondrial (COXMITSUB I) encoded cytochrome c oxidase subunits has been studied in rat hearts subjected to either 12 or 18 wk of coronary artery ligation (CAL). Remodeling induced an increase in expression of the hypertrophic marker gene atrial natriuretic peptide, especially 12 wk after CAL. The mRNA level of the peroxisome proliferator-activated receptor-gamma coactivator-1alpha and its downstream factors, including nuclear respiratory factor 1 and 2, mitochondrial transcription factor A, COXNUCSUB IV, and COXMITSUB I, were significantly reduced in hearts both 12 and 18 wk after ligation compared with sham-operated hearts. Dietary EMD provided immediately after ligation attenuated downregulation of mitochondrial transcription factors with a parallel decrease of hypertrophic marker gene expression. Regression analysis demonstrated a strong positive correlation between the transcription factors and mitochondrial respiratory function. Thus our study shows that the downregulation of mitochondrial transcription factors induced by postinfarction remodeling can be significantly attenuated by NHE-1 inhibition with a further improvement of mitochondrial function in these hearts.
Javadov
Sabzali
S
Dept. of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Univ. of Western Ontario, London, Ontario N6A 5C1, Canada.
Purdham
Daniel M
DM
Zeidan
Asad
A
Karmazyn
Morris
M