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.
Highlights
Cardiovascular disease has always been one of the major diseases threatening human health with the highest morbidity and mortality and remains one of the leading causes of death in the world [1]
We performed Gene Ontology (GO) biological process analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, PPI protein interaction analysis, and so on for differential genes, combined with Quantitative Real-Time PCR (qRT-PCR) experiments to verify the reliability of transcriptomics results. e enrichment results of KEGG pathway suggested that the drug target of Qishen granules (QSG) may be related to cell energy metabolism (Figure 1(a)). e GO results showed that the differential gene function mainly involved ATPnase activity, cytochrome C oxidase activity, NADH dehydrogenase/ubiquinone activity, actin binding, protease binding, and other classical biological processes (Figure 1(b))
Such functions were highly related to mitochondrial functional metabolism and energy metabolism (Figure 1(c)). e OPLS-DA diagram showed that the sequencing data of sham group, model group, and QSG group were completely separated. e difference between groups was obvious and the data was reliable (Figure 1(d))
Summary
Cardiovascular disease has always been one of the major diseases threatening human health with the highest morbidity and mortality and remains one of the leading causes of death in the world [1]. RNA-seq profiling revealed that regulation on cardiac mitochondrial energy metabolism is the main therapeutic effect. 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. E 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. E likely mechanism is the adjustment of PGC-1α/NRF1/TFAM pathway to alleviate oxidative stress in myocardial cells. QSG could regulate mitochondrial dysfunction in ischemia heart tissue to protect cardiac function and structure in HF rats. e likely mechanism is the adjustment of PGC-1α/NRF1/TFAM pathway to alleviate oxidative stress in myocardial cells. erefore, PGC-1α may be a potential therapeutic target for improving mitochondrial dysfunction in HF
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