Mitochondrial reactive oxygen species activate the slow force response to stretch in feline myocardium

作者：Caldiz Claudia I; Garciarena Carolina D; Dulce Raul A; Novaretto Leonardo P; Yeves Alejandra M; Ennis Irene L; Cingolani Horacio E; de Cingolani Gladys Chiappe; Perez Nestor G^*

来源：The Journal of Physiology, 2007, 584(3): 895-905.

DOI：10.1113/jphysiol.2007.141689

When the length of the myocardium is increased, a biphasic response to stretch occurs involving an initial rapid increase in force followed by a delayed slow increase called the slow force response (SFR). Confirming previous findings involving angiotensin 11 in the SFR, it was blunted by AT I receptor blockade (losartan). The SFR was accompanied by an increase in reactive oxygen species (ROS) of similar to 30% and in intracellular Na+ concentration ([Na+](i)) of similar to 2.5 mmol l(-1) over basal detected by H(2)DCFDA and SBFI fluorescence, respectively. Abolition of ROS by 2-mercapto-propionyl-glycine (MPG) and EUK8 suppressed the increase in [Na+](i) and the SFR, which were also blunted by Na+/H+ exchanger (NHE-1) inhibition (HOE642). NADPH oxidase inhibition (apocynin or DPI) or blockade of the ATP-sensitive mitochondrial potassium channels (5HD or glybenclamide) suppressed both the SFR and the increase in [Na+](i) after stretch, suggesting that endogenous angiotensin II activated NADPH oxidase leading to ROS release by the ATP-sensitive mitochondrial potassium channels, which promoted NHE-1 activation. Supporting the notion of ROS-mediated NHE-1 activation, stretch increased the ERK1/2 and p90rsk kinases phosphorylation, effect that was cancelled by losartan. In agreement, the SFR was cancelled by inhibiting the ERK1/2 signalling pathway with PD98059. Angiotensin II at a dose that mimics the SFR (1 nmol l(-1)) induced an increase in center dot O-2(-) production of similar to 30-40% detected by lucigenin in cardiac slices, an effect that was blunted by losartan, MPG, apocynin, 5HD and glybenclamide. Taken together the data suggest a pivotal role of mitochondrial ROS in the genesis of the SFR to stretch.

• 出版日期2007-11-1