Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of p38 MAPK by dual phosphorylation aggravates myocardial ischemic injury and depresses cardiac contractile function. SB203580, an ATP-competitive inhibitor of p38 MAPK and other kinases, prevents this dual phosphorylation during ischemia. Studies in non-cardiac tissue have shown receptor-interacting protein 2 (RIP2) lies upstream of p38 MAPK, is SB203580-sensitive and ischemia-responsive, and aggravates ischemic injury. We therefore examined the RIP2-p38 MAPK signaling axis in the heart. Adenovirus-driven expression of wild-type RIP2 in adult rat ventricular myocytes caused robust, SB203580-sensitive dual phosphorylation of p38 MAPK associated with activation of p38 MAPK kinases MKK3, MKK4, and MKK6. The effect of SB203580 was recapitulated by unrelated inhibitors of RIP2 or the downstream MAPK kinase kinase, TAK1. However, overexpression of wild-type, kinase-dead, caspase recruitment domain-deleted, or kinase-dead and caspase recruitment domain-deleted forms of RIP2 had no effect on the activating dual phosphorylation of p38 MAPK during simulated ischemia. Similarly, p38 MAPK activation and myocardial infarction size in response to true ischemia did not differ between hearts from wild-type and RIP2 null mice. However, both p38 MAPK activation and the contractile depression caused by the endotoxin component muramyl dipeptide were attenuated by SB203580 and in RIP2 null hearts. Although RIP2 can cause myocardial p38 MAPK dual phosphorylation in the heart under some circumstances, it is not responsible for the SB203580-sensitive pattern of activation during ischemia.
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PMID:The role of RIP2 in p38 MAPK activation in the stressed heart. 1831 79

Genome wide association studies have suggested an association of Juxtaposed with another zinc finger gene 1(JAZF1) with type 2 diabetes mellitus (T2DM). As an inhibitor of the TAK1/TR4 signaling pathway, JAZF1 has been shown to be involved in gluconeogenesis, lipid metabolism and insulin sensitivity. However, its role in insulin resistance and atherosclerosis in vivo remains unknown. The present study was designed to investigate in vivo the impact of JAZF1 on insulin resistance-associated dyslipidemia and atherosclerosis. Adenovirus-mediated JAZF1 overexpression was used to characterize the role of JAZF1 in the regulation of lipid metabolism and the development of atherosclerosis in normal chow- or HFD-fed ApoE KO mice. Insulin sensitivity was examined by EHC. Cholesterol de novo synthesis was measured by intraperitoneal [1-(14)C] acetate injection and atherosclerotic plaques were quantified by histological analysis. A dual-luciferase reporter assay was used to assess the ability of JAZF1 to regulate HMGCR transcriptional activity. JAZF1 overexpression improved HFD-induced hepatic insulin resistance in C57BL/6J mice. In HFD-fed ApoE KO mice, JAZF1 overexpression decreased serum cholesterol levels and hepatic cholesterol synthesis by inhibiting CREB-dependent HMGCR promoter transcriptional activity. Analysis of atherosclerotic lesion showed that JAZF1 overexpression had significantly reduced aortic and aortic sinus en face and cross-sectional plaque areas in HFD-fed ApoE KO mice. These data provide the first evidence for an important role of JAZF1 in increasing hepatic insulin sensitivity and preventing atherosclerosis.
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PMID:Overexpression of JAZF1 protected ApoE-deficient mice from atherosclerosis by inhibiting hepatic cholesterol synthesis via CREB-dependent mechanisms. 2549 49