Response to Letter Regarding Article, “Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice”
We appreciate the comments by Cingolani et al on a possible involvement of Na+/H+ exchanger (NHE-1) in signaling mechanisms downstream of cGMP that can mediate cardioprotection after myocardial infarction. These authors previously reported that NHE-1 expression and activity are increased after myocardial infarction in rats (as a result of myocardial acidosis) and that sustained phosphodiesterase-5 (PDE5) inhibition with Sildenafil blunted these effects via a cGMP-dependent protein kinase (PKG)–dependent mechanism.1
We concur with the authors that experimental data indicate a predominant cardioprotective role for both pathways under stress conditions imparted by acidic load (NHE-1 exchanger) or volume/pressure overload (cGMP-PKG signal transduction). The temporal association of reduced NHE-1 activity with increased PKG-1 activity during Sildenafil treatment, which the authors previously reported, suggested a causal relation between both pathways.2 However, additional studies are required to determine whether reduced PKG-mediated NHE-1 phosphorylation contributes to the adverse remodeling associated with PDE5 overexpression in mice subjected to coronary artery ligation.
Although the NHE-1 hypothesis certainly needs to be addressed in future studies, investigators need to keep an open mind because cGMP/PKG-1 signaling also modulates the activity of other ion channels, including the L-type Ca2+ channels3 and the mitochondrial and sarcolemmal potassium channels.4,5 Of interest, Salloum et al reported that PDE5 inhibition with Vardenafil protected rabbit hearts from ischemia/reperfusion injury by opening mitochondrial K(ATP) channels, thereby blunting mitochondrial calcium overload and conferring cardioprotection.6 Finally, growing evidence suggests that dysregulated cGMP signaling plays an important role in disease progression of the hypertrophied or remodeled heart, which likely involves multiple different pathways and protein targets involved in ion channel and calcium homeostasis, altered cAMP- and cGMP-specific PDE isoform activity, and intracellular cGMP compartmentalization.7
Perez NG, Piaggio MR, Ennis IL, Garciarena CD, Morales C, Escudero EM, Cingolani OH, Chiappe de Cingolani G, Yang XP, Cingolani HE. Phosphodiesterase 5A inhibition induces Na+/H+ exchanger blockade and protection against myocardial infarction. Hypertension. 2007; 49: 1095–1103.
Cingolani HE, Ennis IL. Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation. 2007; 115: 1090–1100.
Schroder F, Klein G, Fiedler B, Bastein M, Schnasse N, Hillmer A, Ames S, Gambaryan S, Drexler H, Walter U, Lohmann SM, Wollert KC. Single L-type Ca(2+) channel regulation by cGMP-dependent protein kinase type I in adult cardiomyocytes from PKG I transgenic mice. Cardiovasc Res. 2003; 60: 268–277.
Costa AD, Pierre SV, Cohen MV, Downey JM, Garlid KD. cGMP signalling in pre- and post-conditioning: the role of mitochondria. Cardiovasc Res. 2008; 77: 344–352.
Das A, Smolenski A, Lohmann SM, Kukreja RC. Cyclic GMP-dependent protein kinase Ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. J Biol Chem. 2006; 281: 38644–38652.
Salloum FN, Ockaili RA, Wittkamp M, Marwaha VR, Kukreja RC. Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits. J Mol Cell Cardiol. 2006; 40: 405–411.