p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.

Despite the high and preferential expression of p38γ MAPK in the myocardium, little is known about its function in the heart. The aim of the current study was to elucidate the physiologic and biochemical roles of p38γ in the heart. Expression and subcellular localization of p38 isoforms was determined in mouse hearts. Comparisons of the cardiac function and structure of wild-type and p38γ knockout (KO) mice at baseline and after abdominal aortic banding demonstrated that KO mice developed less ventricular hypertrophy and that contractile function is better preserved. To identify potential substrates of p38γ, we generated an analog-sensitive mutant to affinity tag endogenous myocardial proteins. Among other proteins, this technique identified calpastatin as a direct p38γ substrate. Moreover, phosphorylation of calpastatin by p38γ impaired its ability to inhibit the protease, calpain. We have identified p38γ as an important determinant of the progression of pathologic cardiac hypertrophy after aortic banding in mice. In addition, we have identified calpastatin, among other substrates, as a novel direct target of p38γ that may contribute to the protection observed in p38γKO mice.-Loonat, A. A., Martin, E. D., Sarafraz-Shekary, N., Tilgner, K., Hertz, N. T., Levin, R., Shokat, K. M., Burlingame, A. L., Arabacilar, P., Uddin, S., Thomas, M., Marber, M. S., Clark, J. E. p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.

Paradoxical normoxia-dependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures.

BACKGROUND: Inorganic nitrite dilates small resistance arterioles via hypoxia-facilitated reduction to vasodilating nitric oxide. The effects of nitrite in human conduit arteries have not been investigated. In contrast to nitrite, organic nitrates are established selective dilators of conduit arteries. METHODS AND RESULTS: We examined the effects of local and systemic administration of sodium nitrite on the radial artery (a muscular conduit artery), forearm resistance vessels (forearm blood flow), and systemic hemodynamics in healthy male volunteers (n=43). Intrabrachial sodium nitrite (8.7 µmol/min) increased radial artery diameter by a median of 28.0% (25th and 75th percentiles, 25.7% and 40.1%; P<0.001). Nitrite (0.087-87 µmol/min) displayed conduit artery selectivity similar to that of glyceryl trinitrate (0.013-4.4 nmol/min) over resistance arterioles. Nitrite dose-dependently increased local cGMP production at the dose of 2.6 µmol/min by 1.1 pmol·min(-1)·100 mL(-1) tissue (95% confidence interval, 0.5-1.8). Nitrite-induced radial artery dilation was enhanced by administration of acetazolamide (oral or intra-arterial) and oral raloxifene (P=0.0248, P<0.0001, and P=0.0006, respectively) but was inhibited under hypoxia (P<0.0001) and hyperoxia (P=0.0006) compared with normoxia. Systemic intravenous administration of sodium nitrite (8.7 µmol/min) dilated the radial artery by 10.7% (95% confidence interval, 6.8-14.7) and reduced central systolic blood pressure by 11.6 mm Hg (95% confidence interval, 2.4-20.7), augmentation index, and pulse wave velocity without changing peripheral blood pressure. CONCLUSIONS: Nitrite selectively dilates conduit arteries at supraphysiological and near-physiological concentrations via a normoxia-dependent mechanism that is associated with cGMP production and is enhanced by acetazolamide and raloxifene. The selective central blood pressure-lowering effects of nitrite have therapeutic potential to reduce cardiovascular events.