Abstract 15401: A Novel Mechanism That Modulates Hypertensive Cardiac Hypertrophy via Angiotensin-ii and Sodium-Proton Exchanger-1 Axis
Introduction: Sodium-proton pump exchanger type 1 (NHE-1) is a regulator of intracellular acidity (pHi). Interestingly, NHE-1 is up-regulated in various malignancies and NHE-1 becomes activated during malignant cell transformation, which is via extracellular signal-regulated protein kinases 1/2 mechanism. Angiotensin-II plays a primary role either in tumor progression and development of hypertension and comorbid cardiovascular remodeling via activation of ERK1/2, implicating the presumable link between AngII and NHE-1. In heart, NHE-1 implicated to play a pathophysiological role in cardiac remodeling occurred in diseased myocardium namely, myocardial ischemia and pressure-overloaded heart.
Hypothesis: We therefore reasoned whether NHE-1 may involve in hypertensive cardiac remodeling.
Methods: We compared cardiac NHE-1 expression level between spontaneously hypertensive rat (SHR) and normotensive counterpart (WKY). As a surrogate of NHE-1 activity in cultured cardiomyocytes, intracellular acidity (pHi) was monitored by use of a fluorescence probe for intracellular acidity (pHrodoTM Green AM).
Results: Expression of cardiac NHE-1was significantly higher in SHR than WKY. Interestingly, pharmacological suppression of angiotensin-II (AngII) restored the increase in cardiac NHE-1 of SHR. Next we addressed direct impact of AngII on cardiac NHE-1 expression and its activity by use of cultured cardiomyocytes. AngII directly augmented cardiac NHE-1 expression that was assessed at mRNA and protein levels. Inhibition of NHE-1 promoted intracellular acidification that results in concurrent attenuation of prohypertrophic signaling. Small molecule inhibitor and RNA silencing of NHE-1 attenuated pHi and the AngII-induced cardiomyocyte hypertrophy in terms of cardiomyocyte surface size, surrogate markers [each expression level of brain-type natriuretic peptide (BNP) and β-myosin heavy chain (MYH7)], and prohypertrophic signaling (assessed by phosphorylation levels of ERK, Akt, mTOR, and S6K).
Conclusions: The present study revealed the novel pathophysiological role of NHE-1 and intracellular acidification in the regulation of hypertensive cardiac hypertrophy induced by AngII.
Author Disclosures: Y.K. Bando: None. H. Kawase: None. K. Nishimura: None. T. Murohara: None.
- © 2016 by American Heart Association, Inc.