The mechanism of action of Citrus Bioflavonoids (the main components are hesperidin, neohesperidin, naringin, etc.) in the treatment of cardiovascular diseases involves the synergistic regulation of multi-targets and multi-pathways, which centers on the improvement of vascular function, inhibition of inflammatory response, regulation of metabolic disorders, and protection of cardiac myocytes, etc. The specific details are as follows:
Regulation of vascular tone, lowering blood pressure
Inhibition of angiotensin-converting enzyme (ACE):
Angiotensin-converting enzyme (ACE) can convert angiotensin Ⅰ into the potent constrictor angiotensin Ⅱ, resulting in increased blood pressure. ACE can convert angiotensin Ⅰ into angiotensin Ⅱ which is a potent vasoconstrictor, leading to the increase of blood pressure. Citrus Bioflavonoids such as hesperidin can competitively inhibit the activity of ACE, reduce the production of angiotensin Ⅱ, and at the same time promote the release of bradykinin (vasodilator), thus relaxing blood vessels, reducing peripheral resistance, and exerting antihypertensive effects.
Regulation of calcium channels:
Citrus Bioflavonoids can inhibit calcium ion in-flow in vascular smooth muscle cells, reduce vasoconstriction triggered by elevated intracellular calcium concentration, especially on the resistance vessels (such as small arteries) of the diastolic effect is significant, to further reduce blood pressure.
Improve lipid metabolism, anti-atherosclerosis
Regulate lipid synthesis and catabolism:
Inhibit key enzymes of cholesterol synthesis (e.g. HMG-CoA reductase), reduce endogenous cholesterol production;
Promote lipid catabolism, accelerate fatty acid β-oxidation by activating AMPK signaling pathway, reduce serum triglyceride, low-density lipoprotein cholesterol (LDL-C) level, and raise high-density lipoprotein cholesterol (HDL-C). LDL-C levels, while increasing HDL-C levels, improving the lipid profile.
Inhibition of lipid peroxidation and foam cell formation:
Citrus Bioflavonoids has strong antioxidant activity, which can scavenge free radicals (e.g., superoxide anion, hydroxyl radical) and reduce oxidative modification of LDL-C (ox-LDL); ox-LDL is a key factor in inducing macrophage phagocytosis of lipids and formation of foam cells (atherosclerotic plaques’ core component), so it can inhibit foam cell generation and slow down plaque formation through antioxidant effect. Therefore, ox-LDL can inhibit the generation of foam cells through its antioxidant effect and slow down the progression of plaque.
Inhibition of vascular inflammation and endothelial function protection
Down-regulation of inflammatory factor expression:
Cardiovascular diseases such as atherosclerosis and hypertension are accompanied by endothelial inflammation. Citrus Bioflavonoids can reduce the release of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and other pro-inflammatory factors by inhibiting the NF-κB signaling pathway, and alleviate the inflammatory response of the endothelium.
Protecting vascular endothelial function:
Nitric oxide (NO) secreted by vascular endothelial cells is an important vasodilator, and its synthesis depends on endothelial-type nitric oxide synthase (eNOS). Citrus Bioflavonoids can activate eNOS, promote NO generation, improve endothelial diastolic function; at the same time, inhibit endothelial cell apoptosis, maintain the integrity of the vascular barrier, prevent platelet adhesion and thrombosis.
Protecting cardiomyocytes and improving myocardial ischemia
Reducing myocardial oxidative stress damage:
During myocardial ischemia/reperfusion, a large number of free radicals are generated, which can lead to oxidative damage of myocardial cells. Citrus Bioflavonoids antioxidant properties can scavenge free radicals, reduce the level of lipid peroxidation products (e.g., MDA), and increase the activity of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which can reduce the damage to myocardial cells.
Regulate myocardial energy metabolism:
Citrus Bioflavonoids can promote the uptake and utilization of glucose and fatty acids by cardiomyocytes through activating the AMPK signaling pathway, optimize the energy supply, maintain the stability of energy metabolism of cardiomyocytes especially in ischemic state, and reduce the myocardial necrosis.
Inhibit myocardial fibrosis:
Chronic heart failure and other diseases are often accompanied by myocardial fibrosis (excessive deposition of extracellular matrix). Citrus Bioflavonoids can inhibit the expression of transforming growth factor -β1 (TGF-β1), reduce the proliferation of fibroblasts and collagen synthesis, slow down the process of myocardial fibrosis, and improve cardiac function.