Coronary heart disease, also known as ischemic heart disease (IHD), is one of a group of diseases of the heart blood vessels, which is the top causes of morbidity, mortality, and health-care expenditures in the world. Percutaneous coronary intervention or thrombolysis is an established and crucial therapeutic strategy for IHD [1]. While these treatments can restore blood flow and oxygenation of ischemic myocardium to save myocardial tissue from necrosis, they also have deleterious side effects. Reperfusion therapy can cause ischemia-reperfusion (IR) injury, exacerbating ischemic injury and limiting myocardial salvage [2]. IR injury occurs when the sudden return of blood flow induces the death or apoptosis of ischemic myocardial cells through complex intracellular events, including oxidative stress, imbalanced calcium homeostasis, and exacerbated inflammatory cell infiltration [3]. Unfortunately, the molecular mechanism of IR injury still remains ambiguous.
Mitochondrial energy metabolism, particularly aerobic glycolysis (known as the “Warburg effect”), has been a crucial area of research in cardiovascular disease for decades [4–7]. Research findings have shown that a metabolic shift of increasing glucose oxidation provides beneficial effects in models of myocardial IR injury. In H9c2 rat heart cells, increased aerobic glycolysis has been found to be linked with a decrease in ROS levels and subsequent cell protection against simulated IR injury [5]. Furthermore, switching to aerobic glycolysis can enhance the levels of mitochondrial spare capacity and cell respiratory control ratio, indicating an increased potential to withstand stress conditions in H9c2 cells [7]. Hence, triggering the metabolic shift towards aerobic glycolysis may be consider as one of the potential therapeutic strategies against myocardial IR injury.
Erigeron breviscapus, a traditional Chinese medicinal plant, has been utilized for over 1,000 years in China to treat cardiovascular diseases [8]. Scutellarin (4ʹ, 0, 5, 6-hydroxyl-flavone-7-glucuronide, Scu), the primary active flavonoid extracted from Erigeron breviscapus, is responsible for its pharmacological effects [9]. In-Vivo studies have shown that Scu can alleviate cardiac structure abnormality, improve diastolic dysfunction, promote autophagy, and inhibit inflammatory response and myocyte apoptosis in rat hearts of IR injury [10]. Vitro study showed that Scu administration presented dose-dependently protective effects to enhance proliferation of H9c2 cell, elevate capacity of anti-oxidant and improve potential of mitochondrial membrane via repress IR injury-triggered inflammation injury and oxidative damage [11]. Therefore, Scu has multiple potentially cardio-protective properties.
A variety of biological processes are mediated by non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) [12]. MicroRNAs and long noncoding RNAs have been extensively studied in the field of aerobic glycolysis regulation. For example, miR-206 repressed hexokinase 2 in NSCLC cells to reduce glucose uptake, lactate production and ATP generation [13]. It indicated that miR-142-3p could suppress tumor growth by reducing the Warburg effect in hepatocellular carcinoma [14]. In addition, several miRNAs and lncRNAs regulate aerobic glycolysis, such as lncRNA-Ftx[15], miR-124[16], LINC00152[17], miR-489 and miR-186[18].
In the present study, we first evaluated whether Scu protected against IR injury via enhance Warburg effect in H9c2 cell of IR vitro model. Then, we built a panel of 17 miRNAs [10, 13, 14, 16–29] and 6 lncRNAs [15, 17, 23, 25, 28, 30] that were reported to regulate the Warburg effect. After a series of tests, we identified miR-34c-5p/ALDOA as the key mediators in the protective effects of Scu.