RNA-Seq Profiling to Investigate the Mechanism of Qishen Granules on Regulating Mitochondrial Energy Metabolism of Heart Failure in Rats

Abstract

Background. Qishen granules (QSG) are a frequently prescribed formula with cardioprotective properties prescribed to HF for many years. RNA-seq profiling revealed that regulation on cardiac mitochondrial energy metabolism is the main therapeutic effect. However, the underlying mechanism is still unknown. In this study, we explored the effects of QSG on regulating mitochondrial energy metabolism and oxidative stress through the PGC-1α/NRF1/TFAM signaling pathway. RNA-seq technology revealed that QSG significantly changed the differential gene expression of mitochondrial dysfunction in myocardial ischemic tissue. The mechanism was verified through the left anterior descending artery- (LAD-) induced HF rat model and oxygen glucose deprivation/recovery- (OGD/R-) established H9C2 induction model both in vivo and in vitro. Echocardiography and HE staining showed that QSG could effectively improve the cardiac function of rats with myocardial infarction in functionality and structure. Furthermore, transcriptomics revealed QSG could significantly regulate mitochondrial dysfunction-related proteins at the transcriptome level. The results of electron microscopy and immunofluorescence proved that the mitochondrial morphology, mitochondrial membrane structural integrity, and myocardial oxidative stress damage can be effectively improved after QSG treatment. Mechanism studies showed that QSG increased the expression level of mitochondrial biogenesis factor PGC-1α/NRF1/TFAM protein and regulated the balance of mitochondrial fusion/fission protein expression. QSG could regulate mitochondrial dysfunction in ischemia heart tissue to protect cardiac function and structure in HF rats. The likely mechanism is the adjustment of PGC-1α/NRF1/TFAM pathway to alleviate oxidative stress in myocardial cells. Therefore, PGC-1α may be a potential therapeutic target for improving mitochondrial dysfunction in HF.

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…Optic atrophy 1 (OPA1), which participates in mitochondrial fusion, and fission 1 (FIS1), which participates in mitochondrial fission, could also be explored to understand the mechanistic effects of the drug on mitochondrial biogenesis. The expression of these proteins were significantly attenuated (except for FIS1, which was upregulated) in a murine model of heart failure ( He et al, 2021 ). The effects of the drug on survivor activating factor enhancement (SAFE) signaling pathway, which participates in promoting cardiomyocyte survival ( Hadebe et al, 2018 ) can also be investigated.…”