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

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Peart, Jason N
Pepe, Salvatore
Reichelt, Melissa E
Beckett, Nikkie
Hoe, Louise See
Ozberk, Victoria
Niesman, Ingrid R
Patel, Hemal H
Headrick, John P
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2014
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Abstract

Changes in cytoprotective signaling may influence cardiac aging, and underpin sensitization to ischemic insult and desensitization to 'anti-ischemic' 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. 2-4mo) and human atrial tissue (75Რvs. 55Ჹrs) 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 (4nM phorbol 12-myristate 13-acetate; PMA). In contrast, p38-mitogen activated protein kinase (p38-MAPK) activation (1占anisomycin), mitochondrial ATP-sensitive K(+) channel (mKATP) opening (50占diazoxide) and permeability transition pore (mPTP) inhibition (0.2占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 3߬ GSK3߻ 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.

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Experimental Gerontology

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50

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Biomedical and clinical sciences

Cell physiology

Health sciences

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