The mechanism of BAF60c in myocardial metabolism through the PGC1α/PPARα/mTOR signaling pathway in rats with heart failure

BRM-associated factor (BAF) 60c promotes muscle glycolysis and improves glucose homeostasis. This study explored the mechanism of BAF60c in heart failure (HF). Fetal/adult rat models of HF were established, and the levels of cardiac contractile proteins and energy metabolism-, oxidative metabolism- and glycolysis-related factors were detected. Overexpression/siRNA BAF60c plasmids were injected into adult HF rats to estimate myocardial glucose uptake, high-energy phosphate contents, mitochondrial function, and cell proliferation and apoptosis. The overexpression/siRNA BAF60c plasmids were transfected into cardiac hypertrophic H9C2 cells to explore the in vitro effects. The interaction of BAF60c and PGC1α was detected. The results suggested that adult HF rats presented increased levels of fetal proteins (ssTnI and fTnT), BAF60c and glycolysis-related factors, and reduced levels of cardiac contractile proteins, PGC1α, PPARα, and oxidative metabolism-related factors. BAF60c knockdown improved glucose uptake, maintained the oxidative metabolism/glycolysis balance, promoted H9C2 cell proliferation, and inhibited apoptosis. PGC1α interacted with BAF60c. Knocking down BAF60c also activated the PGC1α/PPARα/mTOR pathway. Overexpression of PGC1α decreased the damage to H9C2 cells caused by BAF60c. Altogether, BAF60c downregulation activated the PGC1α/PPARα/mTOR pathway, maintained the oxidative metabolism/glycolysis balance and improved mitochondrial function in rat models of HF. This study may offer novel insights into HF treatment.

Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice

Using an adult mouse aortic-banded model of pressure-overload hypertrophy and isolated cardiomyocyte mechanics studies, we examined the hypothesis that contractile depression is due to altered cardiac contractile proteins rather than changes in left ventricular (LV) geometry, loading, or the extracellular matrix. FVB mice were banded at the transverse aortic arch or sham operated and studied after 7 days. In nine animals the gradient across the aortic band averaged 47 +/- 4 mmHg. Compared with sham-operated controls, banded animals had increased LV weight-to-body weight ratio (2.8 +/- 0.1 and 3.5 +/- 0.1, respectively; P = 0.035). Left ventricles from additional age-matched groups of mice that underwent identical surgical procedures were examined for altered transcriptional control of myosin heavy chains (MHCs). beta-MHC protein content increased (15 +/- 2%) vs. shams (3.8 +/- 2%; P = 0.004). Dot blots of LV RNA showed a corresponding increase in beta-MHC transcripts in banded animals (15.8 +/- 2%) vs. controls (5.7 +/- 2%; P = 0.012). Contractile performance was assessed using enzymatically disaggregated isolated LV myocytes paced at 0.5 Hz. There was no difference in percentage myocyte shortening between banded (8.6 +/- 0.5%) and control (9.1 +/- 0.5%) animals. However, maximal velocity of contraction was depressed after aortic banding (129 +/- 11 vs. 233 +/- 28 microns/s; P = 0.007), as was velocity of relaxation (105 +/- 11 vs. 188 +/- 22 microns/s; P = 0.007). These results suggest that depressed myocyte contractility after induction of pressure-overload hypertrophy in aortic-banded mice may be, in part, a consequence of transcriptional upregulation of the beta-MHC.