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.
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Ling
L
Gao
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Le
L
Chen
Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences Ministry of Education, Beijing, China.
Zhi-Zhen
ZZ
Lu
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Hong
H
Gao
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Lan
L
Wu
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Yi-Xiong
YX
Chen
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Cai-Mei
CM
Zhang
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Yu-Kun
YK
Jiang
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and.
Qing
Q
Jing
Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences Ministry of Education, Beijing, China.
You-Yi
YY
Zhang
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine Shanghai, China; and htyang@sibs.ac.cn.
Huang-Tian
HT
Yang
D000185:Actinin / Q000378:metabolism; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
D000185:Actinin; D058668:Adrenergic alpha-1 Receptor Antagonists; D004318:Doxycycline; D020778:Matrix Metalloproteinase 2; D011224:Prazosin; D051744:Protein Kinase C-epsilon; D018340:Receptors, Adrenergic, alpha-1; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4
intermittent hypobaric hypoxia; ischemia-reperfusion injury; matrix metalloenzymes-2; mitochondria; α1-adrenoceptors