title: Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium.
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.
authors: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Australia.
authors: Jason N
authors: JN
authors: Peart
authors: Heart Research, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
authors: Salvatore
authors: S
authors: Pepe
authors: Department of Physiology, University of Melbourne, Parkville, VIC, Australia.
authors: Melissa E
authors: ME
authors: Reichelt
authors: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Australia.
authors: Nikkie
authors: N
authors: Beckett
authors: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Australia.
authors: Louise
authors: L
authors: See Hoe
authors: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Australia.
authors: Victoria
authors: V
authors: Ozberk
authors: VA San Diego Healthcare System, San Diego, USA.
authors: Ingrid R
authors: IR
authors: Niesman
authors: VA San Diego Healthcare System, San Diego, USA; Department of Anesthesiology, University of California San Diego, USA.
authors: Hemal H
authors: HH
authors: Patel
authors: Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Australia. Electronic address: j.headrick@griffith.edu.au.
authors: John P
authors: JP
authors: Headrick
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D009924:Organ Culture Techniques; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D043562:Receptors, G-Protein-Coupled; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases
keywords: AKT; Aging; CAV-3; Cardioprotection; Caveolae; Cyt c; ERK1/2; G-protein coupled receptor kinase 2; G-protein coupled receptors; GRK2; GSK3β; Hormesis; Ischemia mitochondria; MAPK/ERK kinase; MEK; PI3K; PKC; PKG; PLC; PLD; Protein kinase; RTK; Ras homolog family member A; RhoA; Stress-resistance; caveolin-3; cytochrome c; eNOS; endothelial nitric oxide synthase; extracellular signal-regulated kinase 1/2; glycogen synthase kinase 3β; mK(ATP); mPTP; mTOR; mechanistic target of rapamycin; mitochondrial ATP-gated K(+) channels; mitochondrial permeability transition pore; p38; p38-mitogen activated protein kinase; p70 ribosomal protein S6 kinase; p70s6K; phosphoinositide 3-kinase; phospholipase C; phospholipase D; protein kinase B; protein kinase G; protein kinase c; receptor tyrosine kinase