Activation of Pyruvate Dehydrogenase (PDH) activity reduces expression of β-Myosin Heavy Chain (β-MHC) in hypertrophied rat heart

Objectives: The carnitine-palmitoyl-transferase (CPT1) inhibitor etomoxir has been used in human heart failure studies, but side effects required termination. In hypertrophied rat heart, etomoxir was improved contractile function by preventing a gene expression shift from β-MHC to α-MHC. We tested whether this shift in gene expression is caused by a shift in substrate oxidation.

Material and Methods: We performed banding of the aortic arch in adult rats to induce hypertrophy. In the experimental groups, rats were either treated with etomoxir (29.5µmol/kg/day for 10 days) or with 10j (N-[2-Chloro-4-(piperazine-1-sulfonyl)-phenyl]-(R)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide, 60µmol/kg/day) for 10 days, an inhibitor of pyruvate-dehydrogenase-kinase. Sham-operated animals served as controls. One week after banding, hearts were analyzed for PDH- and CPT1-activity and expression of α- and β-MHC by real time RT-PCR (Taqman).

Results: Aortic banding caused an increase in heart to body weight ratio (g/kg) from 3.30±0.10 (n=8) to 4.43±0.10 (n=18). The presence of hypertrophy was verified by echocardiography. Total CPT-1- and PDH-activities were the same in all groups. Both etomoxir and 10j increased the PDH-activity status from 27.4±3.2% (n=9) to 61.7±13.1% (n=5) and 82.7±7.5% (n=4), respectively. Aortic banding caused a 2-fold increase in β-MHC expression and a 37% reduction in α-MHC expression (using β-actin as reference). Both etomoxir and 10j prevented the increase in β-MHC expression, but did not affect α-MHC expression. Contractile function was the same in all groups.

Conclusions: We conclude that modulation of glucose oxidation affects the expression of contractile proteins, a mechanism which may be exploited clinically.