Danqi Pill Protects Against Heart Failure Post-Acute Myocardial Infarction via HIF-1α/PGC-1α Mediated Glucose Metabolism Pathway

Abstract

Aim: Heart failure (HF) post-acute myocardial infarction (AMI) leads to a large number of hospitalizations and deaths worldwide. Danqi pill (DQP) is included in the 2015 national pharmacopoeia and widely applied in the treatment of HF in clinics in China. We examined whether DQP acted on glucose metabolism to protect against HF post-AMI via hypoxia inducible factor-1 alpha (HIF-1a)/peroxisome proliferator-activated receptor a coactivator (PGC-1a) pathway. Methods and Results: In this study, left anterior descending (LAD) artery ligation induced HF post-AMI rats and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 cell model were structured to explore the efficacy and mechanism of DQP. Here we showed that DQP protected the heart against ischemic damage as evidenced by improved cardiac functions and attenuated inflammatory infiltration. The expressions of critical proteins involved in glucose intake and transportation such as GLUT4 and PKM2 were up-regulated, while negative regulatory proteins involved in oxidative phosphorylation were attenuated in the treatment of DQP. Moreover, DQP upregulated NRF1 and TFAM, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate (ATP) level. The protection effects of DQP were significantly compromised by HIF-1a siRNA, suggesting that HIF-1a signaling pathway was the potential target of DQP on HF post-AMI. Conclusions: DQP exhibits the efficacy to improve myocardial glucose metabolism, mitochondrial oxidative phosphorylation and biogenesis by regulating HIF-1a/PGC-1a signaling pathway in HF post-AMI rats.

Natural products from traditional Chinese medicine for the prevention and treatment of heart failure: progress and perspectives

“…Angiotensin II in rat cardiac fibroblasts [114] NOX↓ LPS in mice [115] Astragaloside IV(AS-IV) TRPM7 ↓→Collagen ↓ ISO in rats; Hypoxia or ISO in fibroblasts [116] ROS-mediated MAPK↓ ISO in rat [105] ROS↓→cardiotrophin-1↓→Collagen ↓ ISO in cardiac fibroblasts [117] Ligaturing LAD in rat [98] TXB2↓, PGI2↑ Ligaturing LAD in rat [119] Qishen Yiqi Dripping Pill (QSYQ) NF-κB↓, JAK1↓ and AKT↓ Ligaturing LAD in rats [112] Danhong injection NF-κB↓→TNF-α, IL-1β, and IL-6↓ Ligaturing LAD in rat [120] Tanshinone IIA TLR4-NF-κB↓ Ligaturing LAD in mice [121] SIRT1↑→TNF-α and IL-6↓ TAC in rat [122] Astragaloside IV(AS-IV) TLR4/NF-κB ↓ ISO in rats [96,123] NF-кB signaling ↓, PI3K/AKT↑→TNF-α↓ LPS in mice [124] Ouabain IL-6↓, TNF-alpha↓ LPS in mice [125] Anti-cardiomyocyte death Fuzhengkangfu decoction Bcl-2↑, cleaved caspase-3↓ Doxorubicin in H9C2 [126] Qili Qiangxin Capsule Fas↓, cleaved caspase-3↓ Ligaturing LAD in rat [127] Shengmai injection ER stress↓ →caspase-12↓ Doxorubicin in rat [128] Tanshinone IIA/ Bcl-X↓, cleaved caspase-3↓ Abdominal aortic coarctation in rat, Doxorubicin in cardiomyocyte [129,130] Nrf2↑→p38 and mTOR signaling↓ TAC in mice [131] AMPA↑→Bax, cleaved caspase-3↓ LAD in rat, H2O2 in H9C2 [132] Astragaloside IV(AS-IV) Calpain-1 and ROS ↓→Bcl-2/Bax↑, MMP ↑ ISO in rats or H9C2 cells study showed that Zhenwu Tang delayed ventricular hypertrophy by suppressing the expression of BNP, pextracellular signal-regulated kinase 1/2 (ERK1/2), p-p38 and p-JNK [86].…”

“…It was reported that YiQiFuMai powder injection (YQFM), a traditional Chinese medicine prescription redeveloped based on Sheng-Mai-San, could decrease the content of malondialdehyde (MDA) [97]. Moreover, Danqi Pill protects against HF induced myocardial infarction by improving myocardial glucose metabolism, mitochondrial oxidative phosphorylation and biogenesis, which is associated with regulation of the hypoxia-inducible factor-1alpha (HIF-1α)/peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) signaling pathway [98]. Furthermore, Shengmai injection restored the activity of superoxide dismutase (SOD), and glutathione reductase (GSR) in cardiomyocytes with H 2 O 2 -induced oxidative stress by activating AKT and the ERK1/2 pathway [99].…”

“…According to a previous study, the Danqi pill downregulated the expression of phospholipase A2 (PLA2), cyclooxygenase 2 (COX-2) and NF-κB in the inflammatory pathway in a model of coronary heart disease [118]; however, the underlying mechanism remains elusive. A recent study showed that the Danqi pill could improve cardiac functions and attenuate inflammatory infiltration by regu-lating HIF-1α/PGC-1α signaling pathway in HF post-AMI rats [98]. Furthermore, the Danqi pill downregulated the expression of thromboxane B2 (TXB2) and upregulated the expression of prostaglandin I2 (PGI2) to suppress inflammation [119].…”

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

“…By binding with NRF1/2, PGC-1α acted on the promoter of TFAM, thereby promoting mitochondrial DNA replication and transcription, regulating mitochondrial biosynthesis, and stimulating mitochondrial proliferation [10]. In addition, the homeostasis of TFAM plays a vital role in maintaining the normal electron transfer of the intracellular respiratory chain, which ensures the stability of cell energy metabolism [11,12].…”

Astragaloside IV protects cardiomyocytes against hypoxia injury via HIF-1α and the JAK2/STAT3 pathway

“…Its upregulation enhances erythropoiesis, modulation of vascular tone, glycolysis, and angiogenesis (22). Past studies have shown a significant increase in HIF-1α in tunnel positioning areas surrounding the infarct in human ischemic heart tissues and heart failure (HF) post-acute myocardial infarction (AMI) rats (22,23). There have also been reports showing that HIF-1α activation mediated through prolyl 4-hydroxylase-2 (PHD2) gene silencing by siRNA treatment attenuates myocardial ischemia-reperfusion injury (IRI) (24).…”