alexa SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart: pressure-related effects.


Journal of Clinical & Experimental Cardiology

Author(s): Baban B, Liu JY, Mozaffari MS

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Abstract BACKGROUND: Systemic hypertension and the associated increased myocardial load/mechanical stress are common in patients with coronary heart disease. Thus, unraveling of mechanosensitive molecular mechanisms that determine cell fate in the setting of cardiac tissue injury is of scientific and clinical relevance. We tested the hypothesis that the prosurvival, mechanosensitive, serum glucocorticoid-regulated kinase-1 (SGK-1) is a pivotal determinant of pressure-related inflammatory response and cell fate in the ischemic-reperfused heart. METHODS: Langendorff-perfused rat hearts were subjected to an ischemia reperfusion (IR) insult, at 80 or 160cm water, with perfusate lacking or containing the SGK-1 inhibitor GSK650394A (1 μM); normoxic hearts served as controls. Thereafter, hearts tissues were used for Western blotting or cardiac cells were prepared for flow cytometry and immunofluorescent studies. RESULTS: An IR insult (i) reduced phosphoSGK-1 (active and protective) in association with disruption of mitochondrial membrane potential (ψm) and increased apoptosis and necrosis and (ii) increased expressions of growth-arrest and DNA damage-associated protein 153 (GADD153; a determinant of inflammation and cell death) and the proinflammatory cytokine interleukin (IL) 17; these effects were greater at high pressure. On the other hand, the anti-inflammatory cytokines IL-10 and IL-27 increased more in ischemic-reperfused hearts subjected to low pressure. SGK-1 inhibition further reduced phosphoSGK-1, increased GADD153 and IL-17, and reduced IL-10 and IL-27 in association with augmented disruption of ψm and exacerbated cell death; these effects were greater at low pressure. CONCLUSIONS: The results indicate a major pressure-related role for SGK-1 in regulating inflammation and cell fate in the ischemic-reperfused heart. This article was published in Am J Hypertens and referenced in Journal of Clinical & Experimental Cardiology

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