Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium

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• 作者：Jason N. Peart ; Salvatore Pepe ; Melissa E. Reichelt ; Nikkie Beckett ; Louise See Hoe ; Victoria Ozberk ; Ingrid R. Niesman ; Hemal H. Patel ; John P. Headrick
• 关键词：AKT ; protein kinase B ; CAV-3 ; caveolin-3 ; Cyt c ; cytochrome c ; eNOS ; endothelial nitric oxide synthase ; ERK1/2 ; extracellular signal-regulated kinase 1/2 ; GRK2 ; G-protein coupled receptor kinase 2 ; GSK3尾 ; glycogen synthase kinase 3尾 ; MEK ; MAPK/ERK kinase ; mKATP ; mitochondrial ATP-gated K+ channels ; mPTP ; mitochondrial permeability transition pore ; mTOR ; mechanistic target of rapamycin ; p38 ; p38-mitogen activated protein kinase ; p70s6K ; p70 ribosomal protein S6 kinase ; PI3K ; phosphoinositide 3-
• 刊名：Experimental Gerontology
• 出版年：February, 2014
• 年：2014
• 卷：50
• 期：Complete
• 页码：72-81
• 全文大小：1071 K

文摘

Changes in cytoprotective signaling may influence cardiac aging, and underpin sensitization to ischemic insult and desensitization to 鈥榓nti-ischemic鈥?therapies. We tested whether age-dependent shifts in ischemia-reperfusion (I-R) tolerance in murine and human myocardium are associated with reduced efficacies and coupling of membrane, cytoplasmic and mitochondrial survival-signaling. Hormesis (exemplified in ischemic preconditioning; IPC) and expression of proteins influencing signaling/stress-resistance were also assessed in mice. Mouse hearts (18 vs. 2-4 mo) and human atrial tissue (75 卤 2 vs. 55 卤 2 yrs) exhibited profound age-dependent reductions in I-R tolerance. In mice aging negated cardioprotection via IPC, G-protein coupled receptor (GPCR) agonism (opioid, A₁ and A₃ adenosine receptors) and distal protein kinase c (PKC) activation (4 nM phorbol 12-myristate 13-acetate; PMA). In contrast, p38-mitogen activated protein kinase (p38-MAPK) activation (1 渭M anisomycin), mitochondrial ATP-sensitive K⁺ channel (mK_ATP) opening (50 渭M diazoxide) and permeability transition pore (mPTP) inhibition (0.2 渭M cyclosporin A) retained protective efficacies in older hearts (though failed to eliminate I-R tolerance differences). A similar pattern of change in protective efficacies was observed in human tissue. Murine hearts exhibited molecular changes consistent with altered membrane control (reduced caveolin-3, cholesterol and caveolae), kinase signaling (reduced p70 ribosomal s6 kinase; p70s6K) and stress-resistance (increased G-protein receptor kinase 2, GRK2; glycogen synthase kinase 3尾, GSK3尾; and cytosolic cytochrome c). In summary, myocardial I-R tolerance declines with age in association with dysfunctional hormesis and transduction of survival signals from GPCRs/PKC to mitochondrial effectors. Differential changes in proteins governing caveolar and mitochondrial function may contribute to signal dysfunction and stress-intolerance.