Research progress on the pathogenesis of coronary heart disease and correlation with endothelin and nitric oxide Nanjing Hospital of Nanjing University of Traditional Chinese Medicine (210029) Han Xu
Abstract: Starting from the risk factors and pathogenesis of coronary heart disease, this paper illustrates that ET and NO are important vasoactive substances secreted by vascular endothelial cells, which are important for maintaining normal vasodilation; if endothelial cells are damaged, it can cause imbalance of ET and NO secretion, leading to abnormal vasodilation and contraction, which can eventually lead to the occurrence and development of CHD. Han Xu, Department of Geriatrics, Jiangsu Provincial Hospital of Traditional Chinese Medicine
Coronary atherosclerotic heart disease (CHD) refers to heart disease caused by atherosclerosis of coronary arteries narrowing or blocking the lumen, resulting in myocardial ischemia and hypoxia, which, together with functional changes of coronary arteries, i.e. coronary artery spasm, is collectively called coronary heart disease, or coronary heart disease [1]. Clinically, it is mainly manifested by chest tightness, panic, palpitation, heart pain, shortness of breath, etc., when it belongs to Chinese medicine “chest paralysis”, “heart pain”, “stroke heart pain”, “syncope heart pain”, “syncope heart pain”, “syncope heart pain” and “syncope heart pain”. The main manifestations of the disease include “chest paralysis”, “heart pain”, “stroke heart pain”, “syncope heart pain” and “true heart pain”. Modern research has shown that endothelial function impairment is one of the important risk factors for coronary heart disease. Endothelin (ET) and nitric oxide (NO) are vasoactive factors secreted by vascular endothelium, and ET is the strongest vasoconstrictor with significant vasoconstrictive effect on all organs of human body [2]; while NO is a vasodilatory factor with unique role in regulating vascular tone and improving blood circulation [3].ET and NO, as a pair of balanced factors to maintain vasodilation and contraction, are studied for their role in It is important to study their role in the occurrence and development of CHD.
1.Risk factors of CHD
The current risk factors for atherosclerosis are mainly the following: 1. age and gender: the disease is mostly seen in middle-aged and elderly people over 40 years of age, with a higher incidence in men than in women, but an increased incidence in women after menopause, which may be related to the decrease in estrogen levels; 2. hyperlipidemia: increased total cholesterol, triglycerides, low-density lipoprotein, very-low-density lipoprotein and apolipoprotein B, and increased high-density lipoprotein and Hypertension: according to statistics, the prevalence of hypertension is 3-4 times higher than that of normal blood pressure; 4. Smoking: the incidence and mortality rate of patients who smoke is 2-6 times higher than that of nonsmokers; 5. Diabetes and abnormal glucose tolerance; 6. Obesity; 7. Reduced physical activity: lack of exercise, long-term high mental stress Genetic factors: Patients over 50 years of age have a much higher chance of atherosclerosis in their close relatives; 9. Type A personality: People who are quick-tempered, competitive, and often wary of people have an increased risk of CHD; 10. Hyperhomocysteinemia; 11. Chlamydia pneumoniae infection; 12. Western dietary patterns: Use of foods containing high calories, more animal fats and cholesterol, etc [1].
2. Pathogenesis of CHD
The pathogenesis of CHD has always placed more emphasis on the increase and migration of macrophages, the proliferation and migration of smooth muscle cells in phagocytosis and accumulation of lipids; the proliferation and migration of fibroblasts in the formation of fibrofatty lesions; the adhesion and aggregation of platelets, which contribute to endothelial cell damage and proliferation, thrombosis, and the proliferation and migration of these aforementioned cells. All of these cells release a variety of factors that promote the formation of atherosclerosis through different pathways, as well as the proliferation and migration of these cells, creating a vicious cycle that keeps the lesions moving forward. Thus, there are various theories, including the lipid infiltration theory, the platelet aggregation and thrombosis theory, and the smooth muscle cell cloning theory. In recent years, a consensus has gradually emerged on the “endothelial injury response theory”, which suggests that all major risk factors for CHD eventually damage the intima, and the formation of atherosclerosis is the result of the inflammatory-fibroproliferative response of the intima to the injury.
2.1 The lipid infiltration theory
German pathologist Virchow proposed the “lipid infiltration theory” in 1863, suggesting that increased cholesterol in blood, especially LDL and very low density lipoprotein, passes through LDL receptors in endothelial cells, endothelial cell interstitial space, direct endothelial cell swallowing, damaged endothelial cells with increased permeability and directly exposed to subendothelial tissues of blood flow, etc. invade the arterial wall, causing smooth muscle proliferation, formation of foam cells and finally atheromatous plaques with proliferating fibrous tissue [1]. It was found that the incidence of atherosclerosis increases with the increase in plasma cholesterol levels [4]. Serum low-density lipoprotein cholesterol (LDL-C) levels are positively correlated with the development of atherosclerosis, and the mechanism of occurrence is that LDL can be deposited in blood vessels through apoB100 and extracellular matrix, forming atheromatous plaques [5]. It has been shown that high-density lipoprotein cholesterol (HDL-C) prevents the onset and progression of atherosclerosis.HDL acts as an anti-atherosclerotic agent by transporting cholesterol to the liver and lowering serum cholesterol levels. Oxidized low-density lipoprotein (ox-LDL) is an oxidation product of LDL, and studies have found that the development of atherosclerosis and ox-LDL are closely related, and ox-LDL is one of the important factors causing persistent damage to the vessel wall [6]. After numerous trials and studies, ox-LDL was found to promote foam cell formation [7], induce endothelial cell proliferation and smooth muscle cell proliferation and migration [8-9], stimulate monocyte adhesion to endothelial cells, promote thrombosis, stimulate vasoconstriction, damage endothelial cells, exacerbate the inflammatory response to atherosclerosis and activate transcription factor-kB (NF-kB) [5,8], etc. Multiple pathways promote the development and progression of atherosclerosis.
2.2 Thrombosis and platelet aggregation theory
The thrombosis theory suggests that due to hyperactive local coagulation mechanism, thrombus forms, which coagulates on the arterial wall and is covered by proliferating vascular endothelial cells, becoming part of the arterial wall, and gradually forms atheromatous plaque as the thrombus disintegrates and releases lipids and other substances. The platelet aggregation theory suggests that platelet activation factor (PAF) increases, causing platelets to adhere and aggregate on the intima, releasing thromboxane A2 (TXA2), fibroblast growth factor, platelet-derived growth factor, platelet factor 4 (PF4), factor VIII, PAI-1 and other substances, causing endothelial cell damage as well as invasion of LDL, causing smooth muscle cell proliferation and migration as well as monocyte aggregation, and finally fibroblast proliferation, vasoconstriction, and inhibition of thrombolytic mechanisms, leading to the formation of atherosclerosis [10].
2.3 The endothelial injury response theory
In 1973, Ross et al [11] first proposed the “endothelial injury response” hypothesis, which suggests that endothelial dysfunction is the basis for the pathogenesis of structural damage to the vasculature of severe AS, followed by associated inflammation and damaging changes in the proliferative structures of the vessel wall. The vascular endothelium is the single-cell layer covering the inner surface of blood vessels, which is not only a vascular permeability barrier, but also a multifunctional paracrine and endocrine organ that expresses and secretes a variety of bioactive substances with critical roles in the regulation of vascular tone, antithrombosis, smooth muscle cell growth, immune response, extracellular matrix, and inflammatory response, etc. Normal vascular endothelial function is essential for maintaining cardiovascular Normal endothelial function is essential for maintaining homeostasis of the system. Once endothelial cells lose their normal function under the stimulation of pathological factors (such as oxidized low-density lipoprotein, oxygen free radicals, renin-angiotensin system, homocysteine, etc.), pathophysiological changes such as abnormal vasoconstriction, thrombosis, and vascular hyperplasia will occur. Modern medical research has shown that damage to vascular endothelial function occurs in all stages of atherosclerosis. The vascular endothelium is the largest and exceptionally active endocrine, paracrine and autocrine metabolic organ in the body, which can produce and secrete dozens of biologically active substances and plays an important metabolic and regulatory role in the organism.NO and ET are among the important vasoactive substances, and the diastolic factors represented by both of them work together to maintain the vascular tone [2,12]. Endothelial cells mainly have the following roles: (1) regulating the vasodilatory state; (2) preventing platelet adhesion and thrombosis; (3) regulating vascular cell proliferation; and (4) preventing the penetration of harmful substances and infiltration of inflammatory cells [2,12]. Studies have shown that endothelial function damage is an early event in the development of atherosclerosis, and all risk factors leading to atherosclerosis can cause coronary artery endothelial cell damage. Hyperlipidemia, hypertension, diabetes, smoking, advanced age and family history have been shown to have an impairing effect on coronary artery endothelial function [2]. Vascular endothelial dysfunction can lead to thrombosis and lipid deposition, lipid oxidation, formation of ox-LD L, and ultimately atheromatous plaque [13].
2.4 Smoothened muscle cell cloning theory
This theory was proposed by EP Benditt and JM benditt in 1973, who believed that vascular smooth muscle cells in atherosclerotic plaques are clonal, and smooth muscle cells mutate under the action of some substances such as chemical mutagens, viruses, LDL, platelet-derived growth factors, monocyte growth factors, etc., and continuously divide and proliferate, while engulfing lipids, like benign tumors The atherosclerotic plaque is formed by proliferation and division like a benign tumor. Modern medical research has shown that the proliferation and migration of vascular smooth muscle to the subintima is an important part of the pathological development of atherosclerosis, and is also one of the causes of restenosis after vascular intervention [14].
3. correlation of CHD with ET and NO 3.1 ET and CHD
ET is the most potent vasoconstrictor and has three isomeric peptides, ET-1, ET-2 and ET-3, of which ET-1 is the most active; it has two subtypes of receptors, ET-A and ET-B. When ET-A receptors are excited, vascular smooth muscle contracts, and ET-B receptor excitation can stimulate endothelial cells to release NO and prostacyclin ( PGI2), causing vasodilation. ET first binds to ET-B receptors and causes vasodilation. binding, causing vasodilation, but with increasing ET and ET-A receptors and binding, it can cause strong contraction of vascular smooth muscle, resulting in tissue ischemia and hypoxia [15]. Studies have shown that in coronary atherosclerotic plaques, ET is a highly expressed gene, while NO is a low expressed gene [16]; in patients with chronic ischemic heart disease, ET levels gradually increase with decreasing cardiac function, while NO levels gradually decrease with decreasing cardiac function [17], so atherosclerosis then can cause endothelial cell damage and affect the secretion of ET and other substances. Coronary arteries are very sensitive to ET, and elevated plasma ET levels can cause coronary artery spasm, leading to a significant decrease in coronary blood flow and myocardial ischemic injury, causing angina pectoris. Other studies have shown that ET can stimulate smooth muscle cell DNA synthesis, causing smooth muscle cells to shift from G0 phase to S phase, thus promoting vascular smooth muscle proliferation [18], which can accelerate the development of coronary atherosclerosis.
3.2 NO and CHD
L-arginine (L-Agr) is catalyzed by nitric oxide synthase (NOS) to form L-citrulline and release NO. NO stimulates the formation of c-GMP in vascular smooth muscle, which causes relaxation of vascular smooth muscle and vasodilation, so NO can regulate vascular tone, organ blood flow and blood pressure [3]. Studies have shown that NO can inhibit the formation of ox-LDL from LDL, thus reducing the damage of ox-LDL to the vessel wall; NO has an inhibitory effect on the mitosis of platelet cells and can stimulate the formation of S-NO-t-PA complex, which not only increases the activity of tissue-type fibrinogen activator,but also inhibits the function of platelet aggregation [19]. It was also found that NO can inhibit the adhesion of platelets, monocytes and other substances to vascular endothelial cells and inhibit vascular endothelial cell proliferation; it can relax the myocardium and reduce myocardial diastolic tone, thus reducing the pressure on the coronary arteries due to ventricular filling and increasing coronary blood flow. If endogenous NO production is reduced, it can lead to thickening of coronary and aortic vessel walls and narrowing of the lumen [19]. Numerous studies suggest that abnormal NO secretion is involved in the occurrence and development of atherosclerosis, and reduced NO secretion often causes coronary artery constriction and spasm in patients with CHD, which induces angina pectoris.
In conclusion, endothelial function impairment occurs in all stages of atherosclerosis and plays an important role in the occurrence and development of CHD. Under physiological conditions, vascular endothelial cells release both NO and ET, and ET promotes NO synthesis by endothelial cells, which in turn exerts a negative feedback regulation on ET-induced vasoconstriction, thus acting as an inhibitor of ET synthesis [2]. ET and NO are important for maintaining normal vasodilation and contraction, and are important vasoactive substances secreted by vascular endothelial cells. If endothelial cells are damaged, it can cause an imbalance of ET and NO secretion, resulting in abnormal vasodilation and contraction, which can eventually lead to the occurrence and development of CHD.