P38 MAP Kinase Negatively Regulates the Slow Force Response to Myocardial Stretch by Affecting NHE1 Phosphorylation

VILLA ABRILLE MC; DIAZ RG; ZAVALA M; ENNIS, IL.; PEREZ NG; CINGOLANI HE

Dallas

Congreso; American Heart Association Scientific Sessions 2013; 2013

American Heart Association

Abstract 18043: P38 MAP Kinase Negatively Regulates the Slow Force Response to Myocardial Stretch by Affecting NHE1 Phosphorylation María C Villa-Abrille; Romina G Díaz; Maite Zavala; Irene L Ennis; Néstor G Pérez; Horacio E Cingolani Cntr de Investigaciones Cardiovasculares, Cntr de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas de La Plata (UNLP), La Plata, Argentina Mechanical stretch is an important physiological and pathological stimulus to the heart. Stretch induces a biphasic increase in myocardial force generation: A first phase due to the Frank-Starling mechanism, followed by a slower increase in force called slow force response (SFR). The SFR is blunted by AT1 or ETA receptor blockade, by NHE1 inhibition and by reactive oxygen species scavenging. This suggests that it is the mechanical counterpart of an autocrine/paracrine mechanism involving release of angiotensin II (AngII) and endothelin (ET) leading to redox sensitive NHE1 phosphorylation with its consequent activation. Since previous evidence indicates that p38 MAP kinase (p38) negatively regulates the AngII/ET positive inotropic effect in the heart, we hypothesized that the same mechanism would modulate the magnitude of the SFR. Isolated rat papillary muscles were stretched from 92 to 98 % of Lmax. The SFR was 117 ± 2 % of the initial rapid phase (n=6, P<0.05 vs. rapid phase) and was significantly increased after p38 inhibition with 10 umol/L SB202190 (127 ± 2 %, n=6, P<0.05 vs. control SFR), indicating that p38 negatively regulates the SFR development. Since we previously demonstrated that NHE1 activation is a key factor in the chain of events leading to the SFR, we hypothesized that p38 may be modulating NHE1 activity. As an initial approach, we explored the effect of SB202190 on NHE1 activity after an acidic load (ammonium prepulse) in the absence of bicarbonate. p38 inhibition significantly increased maximal NHE1-mediated proton efflux detected at the onset of the acidic recovery [JH+ (mmol/L/min): 2.35 ± 0.25 (n=5) vs. 3.70 ± 0.39 (n=4), P<0.05]. Consistently, under p38 inhibition myocardial stretch promoted a greater increase in ERK1/2 [in % of non stretched control: 166.26 ± 16.35 (stretch, n=3) vs. 231.74 ± 13.70 (strech+SB202190, n=3), P<0.05], and NHE1 [in % of non stretched control: 119 ± 2 (stretch, n=4) vs. 148 ± 9 (strech+SB202190, n=4), P<0.05] phosphorylation. Our results suggest that under physiological conditions p38 activation after myocardial stretch limits the increase in force during the SFR thorough a mechanism that modulates NHE1 phosphorylation.