Dysfunctional Survival-signaling and Stress-intolerance in Aged Murine and Human Myocardium

Overview

Journal Exp Gerontol

Specialty Geriatrics

Date 2013 Dec 10

PMID 24316036

Citations 31

Authors

Jason N Peart

Salvatore Pepe

Melissa E Reichelt

Nikkie Beckett

Louise See Hoe

Victoria Ozberk

Ingrid R Niesman

Hemal H Patel

John P Headrick

Affiliations

Soon will be listed here.

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. 2-4 mo) and human atrial tissue (75±2 vs. 55±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 μM anisomycin), mitochondrial ATP-sensitive K(+) channel (mKATP) opening (50 μM diazoxide) and permeability transition pore (mPTP) inhibition (0.2 μM 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 3β, GSK3β; 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.

Citing Articles

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