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

Peart, Jason N., Pepe, Salvatore, Reichelt, Melissa E., Beckett, Nikkie, Hoe, Louise See, Ozberk, Victoria, Niesman, Ingrid R., Patel, Hemal H. and Headrick, John P. (2014) Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium. Experimental Gerontology, 50 1: 72-81. doi:10.1016/j.exger.2013.11.015

Author Peart, Jason N.
Pepe, Salvatore
Reichelt, Melissa E.
Beckett, Nikkie
Hoe, Louise See
Ozberk, Victoria
Niesman, Ingrid R.
Patel, Hemal H.
Headrick, John P.
Title Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium
Journal name Experimental Gerontology   Check publisher's open access policy
ISSN 0531-5565
Publication date 2014-02
Sub-type Article (original research)
DOI 10.1016/j.exger.2013.11.015
Open Access Status Not yet assessed
Volume 50
Issue 1
Start page 72
End page 81
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Formatted 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 (75±2 vs. 55±2yrs) 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 (1μM anisomycin), mitochondrial ATP-sensitive K+ channel (mKATP) opening (50μM diazoxide) and permeability transition pore (mPTP) inhibition (0.2μM 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.
Keyword Aging
G-protein coupled receptors
Ischemia mitochondria
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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