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 yr) 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.

‘Opioidergic postconditioning’ of heart muscle during ischemia/reperfusion injury

“…In adult rats, µ-OR are absent. Most of the studies were performed on young animals, whereas intrinsic protective tolerance against I/R injury may fail with age in humans [34,35].…”

Myocardial Tissue Caveolae

“…Myocardial ischemia-reperfusion tolerance declines with age in association with dysfunctional homeostasis and transduction of survival signals. Differential changes in proteins governing caveolae such as reduced Cav-3, cholesterol, and caveolae may contribute to signal dysfunction and stress-intolerance (133).…”

Impaired RISK-GSK3β Pathway is Responsible for Comorbidities by Suppressing the Conditioning Cardioprotection

“…In fact, the age-dependent impairment involves a wide signal transduction changes from the myocardial cell membrane receptors to mitochondrial targets (14), which was illustrated in a systematic and rigorous study by Peart et al Similarly, Zhu et al (31) demonstrated that the phosphorylation levels of Akt and GSK3β were remarkably elevated in the aged rats and isoflurane failed to perform cardioprotection related to incapable of further increasing the survival protein phosphorylation to reduce mPTP opening following IRI. In addition, they tried to use SB-216763 and cyclosporine A (CsA), GSK3β and mPTP inhibitor respectively, but it was a pity that both SB-216763 and CsA failed to reduce myocardial infarct size in the aged rats (32,33).…”

“…Numerous studies indicate that age-related intolerance to IRI is associated with alterations of membrane-sensitive cytoprotective signaling and cardiac mitochondrial function (14,24). Especially, RISK-GSK3β pathway altered in aged hearts will undertake the responsibility for the suppression of conditioning protection (Table 1) .…”

“…The reperfusion injury salvage kinase (RISK) pathway is one of the most active and popular signaling pathways in recent years which have been demonstrated to play an important role in conditioning against IRI in different species including rat (10), rabbit (11), mouse (12), porcine (13) as well as human (14). Since the late 1990s, with the gradually recognition of cell apoptosis playing an important role in the lethal reperfusion injury, investigators have found that the so-called pro-survival anti-apoptotic protein kinases including ERK1/2 and Akt can be activated at the initial of myocardial reperfusion, which promoted the RISK pathway emerging as a concept (15).…”