Activation of α1B-adrenoceptors contributes to intermittent hypobaric hypoxia-improved postischemic myocardial performance via inhibiting MMP-2 activation.

Inhibition of matrix metalloproteinases-2 (MMP-2) activation renders cardioprotection from ischemia/reperfusion (I/R) injury; however, the signaling pathways involved have not been fully understood. Intermittent hypobaric hypoxia (IHH) has been shown to enhance myocardial tolerance to I/R injury via triggering intrinsic adaptive responses. Here we investigated whether IHH protects the heart against I/R injury via the regulation of MMP-2 and how the MMP-2 is regulated. IHH (Po2 = 84 mmHg, 4-h/day, 4 wk) improved postischemic myocardial contractile performance, lactate dehydrogenase (LDH) release, and infarct size in isolated perfused rat hearts. Moreover, IHH reversed I/R-induced MMP-2 activation and release, disorders in the levels of MMP-2 regulators, peroxynitrite (ONOO(-)) and tissue inhibitor of metalloproteinase-4 (TIMP-4), and loss of the MMP-2 targets α-actinin and troponin I. This protection was mimicked, but not augmented, by a MMP inhibitor doxycycline and lost by the α1-adrenoceptor (AR) antagonist prazosin. Furthermore, IHH increased myocardial α1A-AR and α1B-AR density but not α1D-AR after I/R. Concomitantly, IHH further enhanced the translocation of PKC epsilon (PKCε) and decreased the release of mitochondrial cytochrome c due to I/R via the activation of α1B-AR but not α1A-AR or α1D-AR. IHH-conferred cardioprotection in the postischemic contractile function, LDH release, MMP-2 activation, and nitrotyrosine as well as TIMP-4 contents were mimicked but not additive by α1-AR stimulation with phenylephrine and were abolished by an α1B-AR antagonist chloroethylclonidine and a PKCε inhibitor PKCε V1-2. These findings demonstrate that IHH exerts cardioprotection through attenuating excess ONOO(-) biosynthesis and TIMP-4 loss and sequential MMP-2 activation via the activation of α1B-AR/PKCε pathway.

Gao L ，Chen L ，Lu ZZ ，Gao H ，Wu L ，Chen YX ，Zhang CM ，Jiang YK ，Jing Q ，Zhang YY ，Yang HT ... -  《-》

Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion.

Wang ZH ，Chen YX ，Zhang CM ，Wu L ，Yu Z ，Cai XL ，Guan Y ，Zhou ZN ，Yang HT ... -  《-》

Activation of alpha1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes.

Gao H ，Chen L ，Yang HT 《CARDIOVASCULAR RESEARCH》

ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca(2+) overload and contractile dysfunction via the JAK2/STAT3 pathway.

Moderate enhanced reactive oxygen species (ROS) during early reperfusion trigger the cardioprotection against ischemia/reperfusion (I/R) injury, while the mechanism is largely unknown. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) contributes to the cardioprotection but whether it is activated by ROS and how it regulates Ca(2+) homeostasis remain unclear. Here we investigated whether the ROS generated during early reperfusion protect the heart/cardiomyocyte against I/R-induced Ca(2+) overload and contractile dysfunction via the activation of JAK2/STAT3 signaling pathway by using a cardioprotective model of intermittent hypobaric hypoxia (IHH) preconditioning. IHH improved the postischemic recovery of myocardial contractile performance in isolated rat I/R hearts as well as Ca(2+) homeostasis and cell contraction in simulated I/R cardiomyocytes. Meanwhile, IHH enhanced I/R-increased STAT3 phosphorylation at tyrosine 705 in the nucleus and reversed I/R-suppressed STAT3 phosphorylation at serine 727 in the nucleus and mitochondria during reperfusion. Moreover, IHH improved I/R-suppressed sarcoplasmic reticulum (SR) Ca(2+)-ATPase 2 (SERCA2) activity, enhanced I/R-increased Bcl-2 expression, and promoted the co-localization and interaction of Bcl-2 with SERCA2 during reperfusion. These effects were abolished by scavenging ROS with N-(2-mercaptopropionyl)-glycine (2-MPG) and/or by inhibiting JAK2 with AG490 during the early reperfusion. Furthermore, IHH-improved postischemic SERCA2 activity and Ca(2+) homeostasis as well as cell contraction were reversed after Bcl-2 knockdown by short hairpin RNA. In addition, the reversal of the I/R-suppressed mitochondrial membrane potential by IHH was abolished by 2-MPG and AG490. These results indicate that during early reperfusion the ROS/JAK2/STAT3 pathways play a crucial role in (i) the IHH-maintained intracellular Ca(2+) homeostasis via the improvement of postischemic SERCA2 activity through the increase of SR Bcl-2 and its interaction with SERCA2; and (ii) the IHH-improved mitochondrial function.

Wu L ，Tan JL ，Wang ZH ，Chen YX ，Gao L ，Liu JL ，Shi YH ，Endoh M ，Yang HT ... -  《-》

Comparison of human alpha1-adrenoceptor subtype coupling to protein kinase C activation and related signalling pathways.

Taguchi K ，Yang M ，Goepel M ，Michel MC ... -  《NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY》