Abstract
The cardiac Na+/H+ exchanger (NHE1) is a membrane glycoprotein fundamental for proper cell functioning due its multiple housekeeping tasks, including regulation of intracellular pH, Na+ concentration, and cell volume. In the heart, hyperactivation of NHE1 has been linked to the development of different pathologies. Several studies in animal models that reproduce the deleterious effects of ischemia/reperfusion injury or cardiac hypertrophy have conclusively demonstrated that NHE1 inhibition provides cardioprotection. Unfortunately, NHE1 inhibitors failed to reproduce these effects in the clinical arena. The reasons for those discrepancies are not apparent yet. However, a reasonable clue to consider would be that drugs that completely abolish the exchanger activity, including that its essential housekeeping function may not be the best therapeutic approach. Therefore, interventions tending to specifically reduce its hyperactive state without affecting its basal activity emerge as a novel potential gold standard. In this regard, a promising goal seems to be the modulation of the phosphorylation state of the cytosolic tail of the exchanger. Recent own experiments demonstrated that Sildenafil, a phosphodiesterase 5A inhibitor drug that has been widely used for the treatment of erectile dysfunction is able to decrease NHE1 phosphorylation, and hence reduce its hyperactivity. In connection, growing evidence demonstrates cardioprotective properties of Sildenafil against different cardiac pathologies, with the distinctive characteristic of directly affecting cardiac tissue without altering blood pressure. This mini-review was aimed to focus on the regulation of NHE1 activity by Sildenafil. For this purpose, experimental data reporting Sildenafil effects in different animal models of heart disease will be discussed.
Highlights
During the last 40 years, the structure, function, and regulation of the sodium/hydrogen exchanger (NHE) have been deeply studied [1,2,3]
All isoforms share the common fundamental function of protecting cells from intracellular acidification, by means of an electroneutral elimination of one intracellular H+ in exchange for one extracellular Na+, and driven by the transmembrane electrochemical Na+ gradient [3]. This mini review focuses on the ubiquitous isoform 1 (NHE1) of this protein family known as the “cardiac isoform” and its regulation by the cyclic guanosine monophosphate/protein kinase G signaling route, triggered by inhibition of the phosphodiesterase 5A (PDE5A) by Sildenafil
We have briefly reviewed the role of Sildenafil on NHE1 regulation and its possible pathophysiological relevance
Summary
During the last 40 years, the structure, function, and regulation of the sodium/hydrogen exchanger (NHE) have been deeply studied [1,2,3]. All isoforms share the common fundamental function of protecting cells from intracellular acidification, by means of an electroneutral elimination of one intracellular H+ in exchange for one extracellular Na+, and driven by the transmembrane electrochemical Na+ gradient [3] This mini review focuses on the ubiquitous isoform 1 (NHE1) of this protein family known as the “cardiac isoform” and its regulation by the cyclic guanosine monophosphate/protein kinase G (cGMP/PKG) signaling route, triggered by inhibition of the phosphodiesterase 5A (PDE5A) by Sildenafil. Hyperactivity of NHE1 has been found in several diseased states, such as ischemia/reperfusion injury [6] and postischemic cardiac remodeling [6], as well as in pressure overload [13, 14] and hypertensive [15] cardiac hypertrophy Reinforcing all these evidences, preclinical studies have demonstrated that blunting NHE1 activity effectively provided cardioprotection in different models of heart failure [16,17,18,19]. The experimental evidence encourages considering that PDE5A inhibition may conceivably be a suitable target to treat cardiac pathologies
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