Age-associated differences in the inhibition of mitochondrial permeability transition pore opening by cyclosporine A

Abstract

mPTP regulation is dysfunctional in the aged myocardium and this could account for loss of cardioprotection with aging.

Chronic Tempol treatment restores pharmacological preconditioning in the senescent rat heart

“…CsA has been reported to have cardioprotective effects in both experimental and clinical studies (20,47). However, our previous work has shown that cardioprotection by CsA is lost in senescent animals (34). Studies have demonstrated that those CypDdeficient mice are remarkably protected from I/R injury and resistant to mPTP opening (1,41).…”

“…Although the mechanism(s) underlying cardiac preconditioning have not yet been adequately elucidated, transient increases in ROS have been shown to be an early trigger for preconditioning, whereas high levels, as seen ROS in reperfusion, may lead to myocardial stunning, infarction, and apoptosis (10,25,30). In our previous studies, we observed that ROS levels appeared to be constitutively higher in the aged myocardium and that cardioprotection by APC or CsA is clearly lost in the senescent animals (34,42). One potential explanation is that isofluraneinduced mitochondrial ROS production in the aged myocardium is not sufficient to trigger preconditioning.…”

“…In the CsA group, CsA (10 mg/kg) was dissolved in DMSO and administrated over 2 min intravenously 5 min before reperfusion. The dose of CsA was chosen based on our previous studies and those of others, comparing the effectiveness of CsA to protect the myocardium during I/R injury in young and old rats (23,34). Protocol B was designed for measurements of protein oxidative damage, the levels of antioxidant enzymes, cyclophilin D (CypD) protein levels, and measurements of mitochondrial Ca 2ϩ uptake.…”

“…Pharmacological preconditioning would seem a promising strategy to protect the heart, especially in the perioperative period. We and others previously have reported, however, that older animals fail to benefit from anesthetic preconditioning (APC), ischemic preconditioning, or pharmacological preconditioning including cyclosporine A (CsA) (34,37,42,44). This could help explain the failure of preconditioning strategies to alter relevant outcomes in clinical studies (11,48).…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…Indeed, pharmacological mPTP inhibitors failed to produce significant effects in either normal or stressed conditions. For instance, cyclosporin A (CsA) was unable to inhibit carboxyatractyloside‐induced permeability transition in aged mitochondria (García, Zazueta, Martínez‐Abundis, Pavón, & Chávez, 2009) and to prolong the time necessary to induce mPTP opening in isolated mitochondria (Duicu et al., 2013) and in cardiomyocytes isolated from old rats (Liu, Zhu, Brink, Glass, & Rebecchi, 2011). Similarly, the ability of sevoflurane and isoflurane conditioning (Li et al., 2013; Zhu et al., 2010) and of the GSK‐3β inhibitor SB‐216763 (Zhu, Rebecchi, Glass, Brink, & Liu, 2011) to protect against myocardial ischemia–reperfusion injury, which is mediated by inhibition of mPTP opening in young rats, is abrogated in senescent animals.…”