Submitted on May 28, 2008
Revised on October 29, 2008
Accepted on October 29, 2008
Injection of Isolated Mitochondria During Early Reperfusion for Cardioprotection
James D. McCully1*, Douglas B Cowan2, Christina A Pacak3, Ioannis K Toumpoulis4, Haripriya Dayalan4, and Sidney Levitsky
1 Harvard Institutes of Medicine
2 Harvard Medical School
3 Children's Hospital Boston
4 Beth Israel Deaconess Medical Center
* To whom correspondence should be addressed. E-mail: james_mccully{at}hms.harvard.edu.
Previously, we have demonstrated that ischemia induces mitochondrial damage and dysfunction that persist throughout reperfusion and impacts negatively on post-ischemic functional recovery and cellular viability. We hypothesized that viable respiration competent, mitochondria, isolated from tissue unaffected by ischemia and then injected into the ischemic zone just prior to reperfusion would enhance post-ischemic functional recovery and limit infarct size. New Zealand rabbits (n=52) were subjected to 30 minutes equilibrium, 30 minutes regional ischemia (RI) induced by snaring the left anterior descending coronary artery. At 29 minutes of RI, the regional ischemic zone was injected with either injection vehicle (sham control and RI-Vehicle) or with injection vehicle containing mitochondria (7.7x106 ± 1.5x106/mL) isolated from donor rabbit left ventricular tissue (RI-Mito). The snare was released at 30 minutes of RI and the hearts reperfused for 120 minutes. Our results show that left ventricular peak developed pressure and systolic shortening in RI-Mito hearts were significantly enhanced (p<0.05 vs RI-Vehicle) to 75% and 83% of equilibrium value, respectively, at 120 minutes reperfusion as compared to 57% and 62% respectively in RI-Vehicle. CK-MB, cTnI and infarct size/area at risk were significantly decreased in RI-Mito as compared to RI-Vehicle (p<0.05). Confocal microscopy showed that injected mitochondria were present and viable following 120 minutes reperfusion and were distributed from the epi- to the sub-endocardium. These results demonstrate that viable respiration competent, mitochondria, isolated from tissue unaffected by ischemia and then injected into the ischemic zone just prior to reperfusion significantly enhance post-ischemic functional recovery and cellular viability.
