p38-MAP Kinase Negatively Regulates the Slow Force Response to Stretch in Rat Myocardium through the Up-Regulation of Dual Specificity Phosphatase 6 (DUSP6).

ZAVALA M; DIAZ RG; MEDINA, A.J.; ACOSTA MP; ESCUDERO D; ENNIS, I.L.; PÉREZ NG; VILLA-ABRILLE, M.C.

CELLULAR PHYSIOLOGY AND BIOCHEMISTRY : INTERNATIONAL JOURNAL OF EXPERIMENTAL CELLULAR PHYSIOLOGY, BIOCHEMISTRY, AND PHARMACOLOGY.

KARGER

Lugar: Basel; Año: 2019 p. 172 - 185

1015-8987

AbstractBackground/Aims: Myocardial stretch increases cardiac force in two consecutive phases:The first one due to Frank-Starling mechanism, followed by the gradually developed slowforce response (SFR). The latter is the mechanical counterpart of an autocrine/paracrinemechanism involving the release of angiotensin II (Ang II) and endothelin (ET) leading toNa+/H+ exchanger 1 (NHE-1) phosphorylation and activation. Since previous evidenceindicates that p38-MAP kinase (p38-MAPK) negatively regulates the Ang II-induced NHE1 activation in vascular smooth muscle and the positive inotropic effect of ET in the heart,we hypothesized that this kinase might modulate the magnitude of the SFR to stretch.Methods: Experiments were performed in isolated rat papillary muscles subjected to suddenstretch from 92 to 98% of its maximal length, in the absence or presence of the p38-MAPKinhibitor SB202190, or its inactive analogous SB202474. Western blot technique was usedto determine phosphorylation level of p38-MAPK, ERK1/2, p90RSK and NHE-1 (previouslyimmunoprecipitated with NHE-1 polyclonal antibody). Dual specificity phosphatase 6 (DUSP6)expression was evaluated by RT-PCR and western blot. Additionally, the Na+-dependentintracellular pH recovery from an ammonium prepulse-induced acid load was used to assesNHE-1 activity. Results: The SFR was larger under p38-MAPK inhibition (SB202190), effect thatwas not observed in the presence of an inactive analogous (SB202474). Myocardial stretchactivated p38-MAPK, while pre-treatment with SB202190 precluded this effect. Inhibitionof p38-MAPK increased stretched-induced NHE-1 phosphorylation and activity, key eventin the SFR development. Consistently, p38-MAPK inhibition promoted a greater increase inERK1/2-p90RSK phosphorylation/activation after myocardial stretch, effect that may certainlybe responsible for the observed increase in NHE-1 phosphorylation under this condition.