CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
P38 MAP Kinase Negatively Regulates the Slow Force Response to Myocardial Stretch by Affecting NHE1 Phosphorylation
VILLA-ABRILLE MC; DÍAZ RG; ZAVALA M; ENNIS IL; PÉREZ NG; CINGOLANI HE
Congreso; 2013 Scientific Sessions of The American Heart Association; 2013
American Heart Association
Mechanical stretch is an important physiological and pathological stimulus to theheart. Stretch induces a biphasic increase in myocardial force generation: A firstphase due to the Frank-Starling mechanism, followed by a slower increase inforce called slow force response (SFR). The SFR is blunted by AT1 or ETA receptorblockade, by NHE1 inhibition and by reactive oxygen species scavenging. Thissuggests that it is the mechanical counterpart of an autocrine/paracrinemechanism involving release of angiotensin II (AngII) and endothelin (ET) leadingto redox sensitive NHE1 phosphorylation with its consequent activation. Sinceprevious evidence indicates that p38 MAP kinase (p38) negatively regulates theAngII/ET positive inotropic effect in the heart, we hypothesized that the samemechanism would modulate the magnitude of the SFR. Isolated rat papillarymuscles were stretched from 92 to 98 % of Lmax. The SFR was 117 ± 2 % of theinitial rapid phase (n=6, P<0.05 vs. rapid phase) and was significantly increasedafter p38 inhibition with 10 umol/L SB202190 (127 ± 2 %, n=6, P<0.05 vs. controlSFR), indicating that p38 negatively regulates the SFR development. Since wepreviously demonstrated that NHE1 activation is a key factor in the chain ofevents leading to the SFR, we hypothesized that p38 may be modulating NHE1activity. As an initial approach, we explored the effect of SB202190 on NHE1activity after an acidic load (ammonium prepulse) in the absence of bicarbonate.p38 inhibition significantly increased maximal NHE1-mediated proton effluxdetected 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 myocardialstretch 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 thatunder physiological conditions p38 activation after myocardial stretch limits theincrease in force during the SFR thorough a mechanism that modulates NHE1phosphorylation.