Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury.

Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 10(6)/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2-8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.

Microarray and proteomic analysis of the cardioprotective effects of cold blood cardioplegia in the mature and aged male and female.

Recently we have shown that the cardioprotection afforded by cardioplegia is modulated by age and gender and is significantly decreased in the aged female. In this report we use microarray and proteomic analyses to identify transcriptomic and proteomic alterations affecting cardioprotection using cold blood cardioplegia in the mature and aged male and female heart. Mature and aged male and female New Zealand White rabbits were used for in situ blood perfused cardiopulmonary bypass. Control hearts received 30 min sham ischemia and 120 min sham reperfusion. Global ischemia (GI) hearts received 30 min of GI achieved by cross-clamping of the aorta. Cardioplegia (CP) hearts received cold blood cardioplegia prior to GI. Following 30 min of GI the hearts were reperfused for 120 min and then used for RNA and protein isolation. Microarray and proteomic analyses were performed. Functional enrichment analysis showed that mitochondrial dysfunction, oxidative phosphorylation and calcium signaling pathways were significantly enriched in all experimental groups. Glycolysis/gluconeogenesis and the pentose phosphate pathway were significantly changed in the aged male only (P < 0.05), while glyoxylate/dicarboxylate metabolism was significant in the aged female only (P < 0.05). Our data show that specific pathways associated with the mitochondrion modulate cardioprotection with CP in the aged and specifically in the aged female. The alteration of these pathways significantly contributes to decreased myocardial functional recovery and myonecrosis following ischemia and may be modulated to allow for enhanced cardioprotection in the aged and specifically in the aged female.