Abstract
Coronary heart disease (CHD) is the most common and serious illness in the world and has been researched for many years. However, there are still no real effective ways to prevent and save patients with this disease. When patients present with myocardial infarction, the most important step is to recover ischemic prefusion, which usually is accomplished by coronary artery bypass surgery, coronary artery intervention (PCI), or coronary artery bypass grafting (CABG). These are invasive procedures, and patients with extensive lesions cannot tolerate surgery. It is, therefore, extremely urgent to search for a noninvasive way to save ischemic myocardium. After suffering from ischemia, cardiac or skeletal muscle can partly recover blood flow through angiogenesis (de novo capillary) induced by hypoxia, arteriogenesis, or collateral growth (opening and remodeling of arterioles) triggered by dramatical increase of fluid shear stress (FSS). Evidence has shown that both of them are regulated by various crossed pathways, such as hypoxia-related pathways, cellular metabolism remodeling, inflammatory cells invasion and infiltration, or hemodynamical changes within the vascular wall, but still they do not find effective target for regulating revascularization at present. 5′-Adenosine monophosphate-activated protein kinase (AMPK), as a kinase, is not only an energy modulator but also a sensor of cellular oxygen-reduction substances, and many researches have suggested that AMPK plays an essential role in revascularization but the mechanism is not completely understood. Usually, AMPK can be activated by ADP or AMP, upstream kinases or other cytokines, and pharmacological agents, and then it phosphorylates key molecules that are involved in energy metabolism, autophagy, anti-inflammation, oxidative stress, and aging process to keep cellular homeostasis and finally keeps cell normal activity and function. This review makes a summary on the subunits, activation and downstream targets of AMPK, the mechanism of revascularization, the effects of AMPK in endothelial cells, angiogenesis, and arteriogenesis along with some prospects.
Highlights
Coronary heart disease (CHD) is the main cause of death globally; it is estimated that 17.9 million people died of cardiovascular diseases (CVDs) in 2016, representing 31% of all global deaths. e basic pathophysiology process is atherosclerosis, which tends to create plaque and block vascular cavity, resulting in myocardial ischemia, hypoxia or necrosis
Angiogenesis is induced by hypoxia and involves three cells: tip cells, stalk cells, and phalanx cells [3,4,5], while the main stimulus of arteriogenesis is fluid shear stress (FSS), which is sensed by endothelial cells and attracts leukocytes and promotes the phenotype transformation of vascular smooth muscle cells (VSMCs) [6,7,8,9]
After the initiation of ischemia, cardiac or skeletal muscle undergoes a series of molecules and hemodynamical changes triggered by hypoxia-related pathways [10], invasion and infiltration inflammatory cells [73, 74], and cellular metabolism remodeling [75, 76], to promote capillary neogenesis, or arterioles remodeling, and eventually to restore blood perfusion of ischemic zones
Summary
Coronary heart disease (CHD) is the main cause of death globally; it is estimated that 17.9 million people died of cardiovascular diseases (CVDs) in 2016, representing 31% of all global deaths. e basic pathophysiology process is atherosclerosis, which tends to create plaque and block vascular cavity, resulting in myocardial ischemia, hypoxia or necrosis. AMPK, a heterotrimeric complex combined by α, β, c subunits, is activated by upstream kinases and regulated by the ratio of ADP/ATP or AMP/ATP or posttranslational modifications including phosphorylation and ubiquitylation, which exerts vital roles in maintaining energy homeostasis, protecting endothelial cellular function, regulating cellular autophagy, oxidative stress, and aging [19]. Like α and β subunits, c subunits have tissue distribution specificity; c1 subunit is widely expressed in all tissues, whereas c2 and c3 isoforms are mainly abundant in skeletal muscle [40] Both α1 and α2 subunits have a crucial site in r183 and r172, whose phosphorylation is necessary for AMPK maximal activation. Erefore, any cellular metabolic process that reduced ATP levels or increased AMP/ADP can activate AMPK, such as hypoxia, glucose decrease, mitochondrial oxidative stress, or metabolic inhibition of ATP synthesis [20, 45]. Skeletal muscle AMPK knockdown-aged mice show hypoglycemia and hyperketosis during fasting [72]
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