HuoXue QianYang QuTan recipe attenuates myocardial hypertrophy in obese hypertensive rats by regulating MPC1/MCT4 mediated pyruvate-lactate metabolic axis

Background: HuoXue QianYang QuTan Recipe (HQQR) is an effective prescription for the clinical management of myocardial hypertrophy in patients with obesity-related hypertension (OBH). In previous studies, HQQR showed the pharmacological properties of mitochondrial protection, anti-inflammatory, and anti-oxidant in OBH rats, which were closely related to its cardioprotective effects. This study is designed to further explore the molecular mechanisms by which HQQR attenuates myocardial hypertrophy in OBH rats.

Methods: High-fat diet-fed SHR were gavaged with HQQR (5 ml/kg or 10 ml/kg, 3.87 g/ml of original drug) or Valsartan (10 ml/kg, 3 mg/ml of original drug) for 10 weeks. In vitro, the H9C2 cells were stimulated with angiotensin-II (Ang-II) and (or) free fatty acid (FFA) in the absence or presence of HQQR. The effects of HQQR on lipid metabolism, mitochondrial function, glycolysis, pyruvate-lactate axis, and myocardial hypertrophy were examined by immunoblotting, pathological analysis, WGA, oil red O and colorimetric methods. Next, to further explore how HQQR attenuates myocardial hypertrophy, we transfected MPC1 siRNA or MCT4 siRNA into H9C2 cells. Finally, the lactate-stimulated H9C2 cells were treated with HQQR and (or) VB124 (a lactate transporter inhibitor), and the degree of myocardial hypertrophy was evaluated by immunoblotting.

Results: Compared to SHR rats, OBH rats exhibited more pronounced blood pressure, lipid metabolism disorder and myocardial pathology injury, which was attenuated by HQQR treatment. Furthermore, HQQR significantly improved the mitochondrial function, glycolysis, and pyruvate-lactate metabolic axis in OBH rats and Ang-II + FFA-treated H9C2 cells, thereby attenuating myocardial hypertrophy. However, these protective effects of HQQR were attenuated in H9C2 cells transfected with MPC1 siRNA and enhanced in cells transfected with MCT4 siRNA. Next, we found that HQQR dose-dependently inhibited the expression β-MHC and ANP proteins in lactate-stimulated H9C2 cells, and that this effect was further enhanced by combination with VB124.

Conclusion: HQQR inhibits glycolysis and restores pyruvate-lactate metabolism in OBH rats by regulating MPC1/MCT4, thereby attenuating myocardial hypertrophy.

Glycolysis; Myocardial hypertrophy; Obesity-related hypertension; Pyruvate-lactate metabolism; Traditional Chinese medicine.