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A Dual Role of Cyclic GMP in Cardiac Survival Signaling
Author(s) -
Lee SungRyul,
McIntosh Rachel,
Shen Xinagjun,
Chanoit Guillaume,
Zvara David A,
Xu Zhelong
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.787.7
Subject(s) - protein kinase b , cardioprotection , cyclic guanosine monophosphate , protein phosphatase 2 , cgmp dependent protein kinase , protein kinase a , mitochondrial permeability transition pore , gsk 3 , microbiology and biotechnology , chemistry , signal transduction , gsk3b , kinase , phosphatase , medicine , phosphorylation , biology , mitogen activated protein kinase kinase , biochemistry , ischemia , programmed cell death , apoptosis , nitric oxide
Cyclic guanosine 3′5′‐monophosphate (cGMP) plays an important role in cardioprotection against ischemia/reperfusion injury through activation of protein kinase G (PKG). The purpose of this study was to determine the impacts of cGMP on cardiac survival signaling pathways. We found that cGMP prevents the mitochondrial permeability transition pore (mPTP) opening by inactivating glycogen synthase kinase 3â (GSK‐3â) via protein kinase G (PKG) in cardiac H9c2 cells. Although Akt is well known as an important upstream regulator of GSK‐3â and its activation leads to inactivation of GSK‐3â, we found that cGMP negatively regulated Akt activity. We further found that the negative regulatory effect of cGMP on Akt activity is mediated by the protein phosphatase PP2A but not by PKG. While GSK‐3â and Akt are critical for acute cardioprotection, an excessive activation of Akt or GSK‐3â inactivation can also result in cardiac hypertrophy. Therefore, the negative effect of cGMP on Akt activity may serve as an important mechanism leading to prevention of hypertrophy. Taken together, cGMP not only inactivates GSK‐3â through PKG (this leads to acute cardioprotection) but also negatively regulates Akt activity (this may lead to prevention of hypertrophy and heart failure) in cardiac cells. We propose that cGMP is a versatile signal with a dual beneficial role in cardiac survival. This study was supported by NIHR01HL08336