Uncoordinate regulation of PGC-1α and respiratory chain gene expression in the development of heart failure in rats

Aims: Heart failure may be due to a lack of ATP production. Coordinated downregulation of the key regulator of mitochondrial ATP production, PGC-1α has been implicated in the development of heart failure (Garnier et al. J Physiol. 2003). We aimed to assess the expression of PGC-1α and respiratory chain genes as well as contractile activity during the development of pressure-overload hypertrophy and heart failure.

Methods: Aortic banding was performed in male Wistar rats. Pressure-overload hypertrophy was present after two weeks, overt heart failure after 11 weeks as verified by echocardiography. Messenger-RNA expression of PGC-1α, NADH dehydrogenase subunit 2 (NADH-DHsub2) and cytochrome c oxidase (COXIV) was investigated using real-time RT-PCR.

Results: After 2 weeks, rats developed pressure-overload hypertrophy (2.6±0.0 vs. 4.0±0.3; p<0.001), but no signs of heart failure. After 11 weeks, rats developed severe heart failure as indicated by dyspnea, pleural effusions and echocardiographic signs of contractile dysfunction (sham vs. heart failure: LVEDD 7.4±0.5 vs. 9.1±0.6mm, p<0.01; LVESD 4.8±0.4 vs. 7.3±0.6mm, p<0.01; EF 73±5 vs. 45±5%, p<0.01; FS 35±5 vs. 20±3%, p<0.01). Expression of PGC-1α was biphasic, i.e., downregulated in hypertrophied hearts (–40%;p<0.01) and not different from sham in failing hearts (–11%;n.s.). Expression of respiratory chain genes was unaltered all times (Hypertrophy: NADH-DHsub2: +17%, n.s.; COXIV: +23%, n.s.; Heart failure: NADH-DHsub2: +65%, n.s.; COXIV: –24%, n.s.).

Conclusions: The expression patterns of PGC-1α and the respiratory chain genes do not parallel each other during the development of heart failure. Other regulatory processes must be involved in the regulation of ATP production during the development of heart failure.