title: Dual role of cyclic GMP in cardiac cell survival.
abstract: It is well known that cyclic guanosine 3',5'-monophosphate plays an important role in cardioprotection against ischemia/reperfusion injury through activation of protein kinase G (PKG). We found that cGMP prevents the mitochondrial permeability transition pore (mPTP) opening by inactivating glycogen synthase kinase 3β (GSK-3β) via protein kinase G (PKG) in cardiac H9c2 cells. While GSK-3β and its major upstream regulator phosphoinositide 3-kinase (PI3K)/Akt are critical for acute cardioprotection, an excessive activation of PI3K/Akt or GSK-3β inactivation can also lead to cardiac hypertrophy. Here, we show that cGMP not only inactivates GSK-3β through PKG (this leads to acute cardioprotection) but also negatively regulates Akt activity (this may lead to prevention of hypertrophy and heart failure, and the regulation of NO synthesis) in cardiac cells. We further found that the negative regulatory effect of cGMP on Akt activity is not mediated by PKG but may be through up-regulation of protein phosphatase PP2A activity. We propose that cGMP is a versatile signal with dual beneficial role in cardiac cell survival.
authors: Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China. zxu@tijmu.edu.cn
authors: Zhelong
authors: Z
authors: Xu
authors: SungRyul
authors: S
authors: Lee
authors: Jin
authors: J
authors: Han
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D005453:Fluorescence; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000494:pharmacology; D008387:Marine Toxins; D008840:Microfilament Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D002227:Carbazoles; D015815:Cell Adhesion Molecules; D007328:Insulin; D008387:Marine Toxins; D008840:Microfilament Proteins; D010080:Oxazoles; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; C073601:KT 5823; D010768:Phosphoserine; C016276:8-bromocyclic GMP; C059041:calyculin A; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine
keywords: Akt; PKG; PP2A; cGMP; mPTP