RGD Reference Report - Pressure overload regulates expression of cytokines, gammaH2AX, and growth arrest- and DNA-damage inducible protein 153 via glycogen synthase kinase-3beta in ischemic-reperfused hearts.

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Pressure overload regulates expression of cytokines, gammaH2AX, and growth arrest- and DNA-damage inducible protein 153 via glycogen synthase kinase-3beta in ischemic-reperfused hearts.
Authors:	Baban, B Liu, JY Mozaffari, MS
Citation:	Baban B, etal., Hypertension. 2013 Jan;61(1):95-104. doi: 10.1161/HYPERTENSIONAHA.111.00028. Epub 2012 Oct 29.
RGD ID:	8693739
Pubmed:	PMID:23108649 (View Abstract at PubMed)
DOI:	DOI:10.1161/HYPERTENSIONAHA.111.00028 (Journal Full-text)
The growth arrest- and DNA-damage inducible protein 153 (GADD153) regulates both apoptosis and inflammatory response. Importantly, glycogen synthase kinase-3beta (GSK-3beta) may provide a mechanistic link for cellular expression of GADD153, inflammatory response, and cell death. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion injury associated with significant reduction in phosphorylated (inactive) GSK-3beta. This raises the possibility that pressure overload, through a GSK-3beta-dependent mechanism, increases GADD153 expression, thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial ischemia reperfusion injury. Accordingly, Langendorff-perfused rat hearts were subjected to global ischemia reperfusion protocol in the absence or presence of the GSK-3beta inhibitor, lithium chloride (1 mmol/L), with perfusion pressure set at 80 or 160 cmH(2)O; normoxic hearts served as controls. Compared with normoxia, an ischemia reperfusion insult increased expressions of proinflammatory cytokines, gammaH2AX, and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload did the following: (1) reduced interleukin-10 but increased interleukin-17 (cardiomyocytes), without affecting interleukin-23; (2) increased expressions of gammaH2AX and GADD153; (3) decreased 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) aggregates but increased JC-1 monomers (suggestive of reduced mitochondrial membrane potential, psi(m)); and (4) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Treatment with lithium chloride caused a robust increase in interleukin-10, preserved psi(m), and markedly decreased all other parameters with the effect being most prominent for hearts perfused at the high pressure. In conclusion, pressure overload, via a GSK-3beta-dependent mechanism, exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of inflammatory response, DNA injury, and GADD153 expression.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
H2AX	Human	Myocardial Reperfusion Injury	treatment	ISO	H2ax (Rattus norvegicus)		RGD
H2ax	Mouse	Myocardial Reperfusion Injury	treatment	ISO	H2ax (Rattus norvegicus)		RGD
H2ax	Rat	Myocardial Reperfusion Injury	treatment	IDA			RGD

Objects Annotated

Genes (Rattus norvegicus)

H2ax (H2A.X variant histone)

Genes (Mus musculus)

H2ax (H2A.X variant histone)

Genes (Homo sapiens)

H2AX (H2A.X variant histone)

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Pressure overload regulates expression of cytokines, gammaH2AX, and growth arrest- and DNA-damage inducible protein 153 via glycogen synthase kinase-3beta in ischemic-reperfused hearts.