Abstract: Inflammation plays an important role in mediating the onset and progression of atherosclerosis. Risk factors for atherosclerosis such as oxidized lipoproteins, lipid metabolism disorders, hypertension, diabetes, obesity and infections can initiate the inflammatory process and promote its further development. There is a strong link between inflammation and them.
For nearly a century, the idea that lipids are responsible for atherosclerosis has been accepted by most people. However, more and more studies have found that atherosclerotic plaques not only contain lipids but also have a large infiltration of inflammatory cells, characterized by the accumulation of large numbers of monocytes and lymphocytes in the vessel wall, suggesting that inflammation may play an important role in mediating the onset and development of atherosclerosis. Risk factors for atherosclerosis include oxidized lipoproteins, disorders of lipid metabolism, hypertension, diabetes, obesity and infections, which can initiate the inflammatory process and promote its further development. In this article, we will discuss the relationship between inflammation and atherosclerosis risk factors.
1. The role of inflammation in mediating the onset and development of atherosclerosis
In animal models of atherosclerosis, inflammatory markers have been found to be often present along with lipid invasion into the arterial wall. For example, leukocytes, a regulator of defense and inflammation in humans and animals, can appear at the early stages of atherosclerotic lesions. Normal endothelium does not normally cause leukocyte adhesion and aggregation. VCAM-1, in particular, selectively adheres to monocytes and T lymphocytes early in the fatty infiltration of the arterial wall in humans or experimental animals. vCAM-1 is often overproduced during the development of atherosclerosis, whereas genetically engineered VCAM-1-deficient mice do not undergo progression of atherosclerosis [1].
Adhesion molecules are often overproduced at arterial bifurcations that are prone to atherosclerosis. There is evidence that endogenous protective mechanisms against atherosclerosis at arterial bifurcations are disrupted by exposure to turbulence. For example, abnormal fluid shear stress reduces its endothelial-derived NO production, an endogenous diastatic molecule with anti-inflammatory properties that limits the secretion of ICAM-1, VCAM-1, etc. Altered fluid shear stress also induces IL-8 secretion by endothelial cells, which plays a role in the development and progression of acute inflammation and atherosclerosis [2]. In addition to disrupting normal protective mechanisms, turbulence can also increase the secretion of specific leukocyte adhesion molecules (e.g. ICAM-1). The increase in arterial wall pressure can also cause the smooth muscle cells (SMC) of the arterial wall to produce more proteoglycans, which induce the inflammatory response of the body to local lesions by adhering to and oxidizing lipoprotein particles [3].
After adhering to the endothelium, leukocytes migrate to invade the endothelium. Recent studies have identified several chemoattractant molecules that may be associated with this process, for example: monocyte chemoattractant protein-1 (MCP-1) induces the accumulation of monocytes into the diseased intima. t-cell chemoattractants also induce the migration of a variety of lymphocytes into the intima [4]. After invasion into the arterial wall, blood-derived inflammatory cells trigger and sustain a persistent inflammatory response locally. Macrophages can transform into foam cells by phagocytosis of modified or oxidized lipoproteins through scavenger receptors. In addition to MCP-1, macrophage colony-stimulating factor has a role in prompting blood monocytes to differentiate into macrophages that eventually become foam cells. t cells can release inflammatory cytokines such as gamma-interferon and lymphocytotoxin (aka tumor necrosis factor TNF-β). As inflammation progresses, activated leukocytes and endothelial cells release a variety of growth factors, such as platelet-derived growth factor (PDGF), fibrous growth factor (FGF), epidermal growth factor-like factor (EGF-like factor), and transforming growth factor beta (TGF-β), among others. ), among others, which stimulate smooth muscle cells and fibroblasts to proliferate and migrate from the middle layer of the arterial wall into the intima and stimulate these cells to generate new connective tissue, forming intimal fibromuscular proliferative lesions and thus worsening atherosclerosis. Peroxisome proliferator-activated receptor γ (PPARγ), which is widely expressed in tissues, is a biological receptor for thiazolidinedione antidiabetic drugs, mainly regulating adipocyte differentiation, glucose homeostasis. It inhibits the expression of certain pathogenic genes, suppresses monocyte and macrophage function, reduces the production and release of cell adhesion molecules and other inflammatory mediators, thereby inhibiting the proliferation and migration of vascular smooth muscle cells; it can stop the process of atherosclerosis. It is of great importance in the development and progression of atherosclerosis [5].
Inflammation not only promotes the onset and progression of atherosclerosis, but also its complication with acute thrombosis. The vast majority of coronary thrombi that cause fatal myocardial infarction are due to atheromatous plaque rupture. Macrophages activated within the plaque can produce protein hydrolases that degrade the fibrous tissue in the fibrous cap that protects the plaque, weakening the cap and destabilizing the plaque. Gamma-interferon produced by intraplaque activated T lymphocytes can inhibit collagen synthesis by SMCS cells and limit their renewal of collagen fibers that play a role in enhancing plaque stability [6]. Mast cells activated within the plaque affect SMCS cell proliferation by secreting hepatic phospholipid proteoglycans, reducing their number within the plaque [7]. Macrophages can also produce pro-coagulant and thrombogenic tissue factors. Inflammatory regulatory factors can regulate the secretion of tissue factor by regulating the number of macrophages in plaques, suggesting a strong link between arterial inflammation and thrombosis [8].
2, Inflammation and oxidized lipoproteins
A more plausible theory linking lipids and inflammation to atherosclerosis has evolved in recent decades. According to the oxidative hypothesis, low-density lipoproteins (LDL) invade the intima through adherent proteoglycans and subsequently undergo oxidative modifications. Lipid hydroperoxides, hemolytic phospholipids, carbonyl compounds and other biologically active debris are deposited in large quantities in the lipid fraction of plaques, and these modified lipids induce the secretion of adhesion molecules, chemoattractants and preinflammatory factors, and several other inflammatory regulators in macrophages and vascular wall cells. The de-cofactorized fraction of lipoprotein particles in the arterial wall can also be modified into antigenic substances that elicit T-cell responses, thereby triggering specific antigen-antibody immune responses in vivo. Under certain experimental conditions, the use of antioxidants can delay the progression of atherosclerotic damage that occurs in hyperlipidemia, such as COX-2 inhibitors that interfere with the production of prostacyclin, thromboxane and inflammatory factors induced by oxidized LDL [9].
Although the LDL oxidation hypothesis is supported by much experimental evidence, the exact relationship between it and human atherosclerosis remains to be further confirmed. Analysis of modified lipids and proteins extracted from human atheromatous plaques shows that this conclusion is not fully consistent with in vitro experiments. Most of the cell culture experiments investigating the biological effects of oxidized LDL have used oxidation reactions mediated by transmetals, so these findings do not necessarily hold in vivo. Hypochlorous acid-mediated oxidative modifications of lipoproteins are closer to physiological processes than those mediated via transmetallics [10], as leukocyte myeloperoxidase can produce hypochlorous acid in atherosclerotic plaques. Clinical trials aimed at validating treatment with antioxidant vitamins to improve clinical symptoms have not been successfully reported, therefore, the applicability of the LDL oxidation hypothesis to humans remains to be further investigated.
3. Inflammation and disorders of lipid metabolism
Other lipoprotein particles such as very low density lipoprotein (VLDL) and medium density lipoprotein also have potentially atherogenic properties. These lipoprotein particles can be oxidatively modified like LDL. In addition, there is evidence that β-VLDL particles themselves can activate the inflammatory function of endothelial cells [11]. HDL exerts its protective effect against atherogenesis mainly through its reverse cholesterol transport. Moreover, HDL particles can also transport antioxidant enzymes like platelet-activating factor acetylhydrolase and paraoxonase that can destroy oxidized lipids and block the pre-inflammatory effects, playing a protective role against LDL peroxidation.
4, inflammation and hypertension
For atherosclerosis, hypertension is a risk factor second only to lipids. There is growing evidence that, similar to atherosclerosis, inflammation plays an important role in the pathogenesis of hypertension, and thus there is a pathophysiological link between hypertension and atherosclerosis. Angiotensin (AII) and its own vasoconstrictive properties can trigger an inflammatory response in the intima. For example, AII can induce the production of a peroxide anion DD reactive oxygen species in arterial endothelial cells and SMCS, and it can increase preinflammatory factors such as IL-6 and MCP-1 secreted by SMCS, in addition to the leukocyte adhesion molecules ICAM-1 and VCAM-1 secreted by endothelial cells [12]. Angiotensin-converting enzyme inhibitors can benefit patients by blocking to some extent such a pre-inflammatory response pathway.
5. Inflammation and diabetes mellitus
Diabetes mellitus is also a risk factor for atherosclerosis and its importance is increasingly appreciated. The hyperglycemic state of diabetes can trigger some macromolecules to undergo glycosylation modifications, for example, by adding pre-glycan termini (AGE) [13]. The adhesion of proteins modified by AGE to surface receptors such as RAGE (AGE receptor) can increase the amount of pre-inflammatory cytokines such as fibrinogen activation inhibitor-1 (PAI-1) and CRP in vascular endothelial cells [14] and initiate some new pathways of inflammatory response. In addition to hyperglycemia, the diabetic state can exacerbate oxidative effects induced by activated oxygen and carbonyl-containing compounds [15]. Similar to hypertension, diabetes and atherosclerosis can be linked through inflammation.
6, inflammation and obesity
Obesity not only has the tendency to cause insulin resistance and diabetes, but also can cause disorders of lipid metabolism thus leading to the occurrence of atherosclerosis. The high concentration of free fatty acids produced by the intestine can enter the liver through the portal circulation, at the same time, stimulate the hepatocytes to synthesize the lipoprotein VLDL which combines the triglyceride. Adipose tissue can also synthesize cytokines such as TNF-α and IL-6 [16]. Therefore, in addition to insulin resistance and lipoprotein pathways of action, obesity can also rely on itself to aggravate the inflammatory response and atherogenic tendencies.
7, inflammation and infection
Infection can trigger inflammation and promote the further development of atherosclerosis, such as the proven Chlamydia pneumoniae infection [17]. Acute infections can cause hemodynamic changes, hypercoagulability, and alterations in the fibrinolytic system, leading to myocardial ischemic events. Chronic extravascular infections such as gingivitis, prostatitis, and bronchitis can increase the amount of extravascular inflammatory factors and accelerate the progression of atherosclerotic lesions. Intravascular inflammation can also exacerbate the extent of atherosclerotic damage through local inflammatory stimulation of the lesion. Signs of microbial infection are also shown in many atheromatous plaques. These microorganisms can release endotoxins and heat shock proteins, which stimulate the production of more pre-inflammatory factors by vascular endothelial cells and SMCS, and they can also promote the adhesion and migration of leukocytes. Epidemiological investigations of infections show that the risk of cardiovascular disease can be broadly predicted by direct detection of antibodies to Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus or cytomegalovirus.