Activated NHE1 is required to induce early cardiac hypertrophy in mice

Abstract

The Na+/H+ exchanger isoform 1 (NHE1) has been implicated as being causal in cardiac hypertrophy and the protein level and activity are elevated in the diseased myocardium. However, it is unclear whether mere elevation of the protein is sufficient for cardiac pathology, or whether activation of the protein is required. In this study, we examined the comparative effects of elevation of wild type and activated NHE1. Two mouse transgenic models that expressed either a wild type NHE1 protein or an activated NHE1 protein were characterized. Expression of activated NHE1 caused significant increases in heart weight to body weight, apoptosis, cross-sectional area, interstitial fibrosis and decreased cardiac performance. Expression of wild type NHE1 caused a much milder pathology. When we examined 2 or 10-week-old mouse hearts, there was neither elevation of calcineurin levels nor increased phosphorylation of ERK or p38 in either NHE1 transgenic mouse line. Expression of activated NHE1 in intact mice caused an increased sensitivity to phenylephrine-induced hypertrophy. Our results show that expression of activated NHE1 promotes cardiac hypertrophy to a much greater degree than elevated levels of wild type NHE1 alone. In addition, expression of activated NHE1 promotes greater sensitivity to neurohormonal stimulation. The results suggest that activation of NHE1 is a key component that accentuates NHE1-induced myocardial pathology.

Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

“…content [6]. The NHE1 activity contributes to cardiac hypertrophy [61,65,66,100]. Accordingly, cardiac hypertrophy and its progression to heart failure can be strongly reduced by NHE1 inhibitors [1,24,60].…”

Sgk1-Dependent Stimulation of Cardiac Na+/H+Exchanger Nhe1 by Dexamethasone

“…The cardiac Nhe1 has emerged as a key factor in myocardial remodeling [65,66,67]. Enhanced Nhe1 activity contributes to the pathophysiology of myocardial reperfusion injury [68], cardiac insufficiency [69] and cardiac hypertrophy [42,43,70,71,72]. Accordingly, upregulation of Nhe1 may trigger [73] and pharmacological inhibition of Nhe1 counteracts [65,66,67] cardiac hypertrophy and progression to heart failure.…”

Defining the Na+/H+ exchanger NHE1 interactome in triple-negative breast cancer cells

“…The activation of NHE1, and not increased expression of the protein per se, is the critical factor determining NHE1-mediated disease progression [55]. Further to this end, we recently demonstrated that replacement of endogenous NHE1 in MDA-MB-231 cells with a hyperactive NHE1 protein resulted in an increased metastatic behaviour of this cell line [14].…”