| First Author | Karamanlidis G | Year | 2014 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 307 |
| Issue | 9 | Pages | H1307-16 |
| PubMed ID | 25172896 | Mgi Jnum | J:218703 |
| Mgi Id | MGI:5618213 | Doi | 10.1152/ajpheart.00280.2014 |
| Citation | Karamanlidis G, et al. (2014) Promoting PGC-1alpha-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts. Am J Physiol Heart Circ Physiol 307(9):H1307-16 |
| abstractText | Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha pathway. To test whether PGC-1alpha is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1alpha ( approximately 3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1alpha overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice. |
