Abstract 13221: Stem Cell Therapies for Coronary Collateral Growth in Zucker Obese Fatty Rats: Redox Modulator MitoNEET as a Therapeutic Target
Stem cell-based regenerative therapies for ischemic heart disease in humans have yielded disparate results ranging from improvement to exacerbation of injury. These results are a “disconnect” from animal studies showing positive effects; however, most animal studies were performed in normal models without metabolic disease and oxidative stress. Accordingly, we hypothesized that amelioration of oxidative stress via “braking” metabolism of stem cells (less production of O2-derived radicals) would facilitate stem cell therapies. To test this, we studied coronary collateral growth (CCG) in Zucker obese fatty rats (ZOF), a model of the metabolic syndrome. Compared to lean control rats, ZOF demonstrate poor CCG in response to repeated, transient coronary occlusions (RI), even when combined with stem cell therapy. To reduce metabolism in stem cells, we targeted mitoNEET (a mitochondrial protein that modulates O2 metabolism, Complex I activity, and reactive oxygen species [ROS] production) with mitoNEET Ligand-1 (NL-1), analyzing cardiac stem cell survival amidst oxidative stress, and CCG in ZOF following RI. C-kit+ Lin- cardiac stem cells (CSCs) were treated with 10 μM NL-1 for 15 min prior to 4 hrs incubation in 500 μM H2O2. Trypan blue exclusion showed that NL-1 significantly improved CSC survival compared to vehicle (% survival normalized to untreated control = 61.63 vs. 30.43; p < 0.05; N=4). NL-1 also reduced maximal O2 consumption of CSCs (Seahorse XF-24), indicating attenuated ROS production due to decreased electron entry into Complex I (N=3). To study the in vivo effects of NL-1 on stem cell induction of CCG, ZOF received intramyocardial injection of stem cells with or without daily injections (5 mg/kg, sc) during the entire protocol. LV fractional shortening improved significantly in the stem cell+NL-1-treated group compared to stem cells alone (13.72% vs. 8.0%; p < 0.05; N=5 each group). However, these improvements did not correlate with an increase in collateral-dependent blood flow to the ischemic region of the myocardium, either with or without stem cell treatment. These data allude to the propitious potential of mitochondrial targets as means of improving stem cell-based therapies in the presence of metabolic disease with oxidative stress.
- © 2013 by American Heart Association, Inc.