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Cardiovascular and Inflammation


Introduction of inflammation in cardiovascular

In past studies of cardiovascular disease, atherosclerosis was thought to be caused by the formation of lipid deposits in the walls of blood vessels. This accumulation then blocks the blood vessels, affecting blood transport and ultimately leading to cardiovascular disease, such as myocardial infarction or stroke. Later studies found that atherosclerosis is caused by chronic inflammation. Atherosclerosis is the most common pathological basis for coronary heart disease and other cardiovascular diseases. Therefore, it can be said that the inflammatory response is closely related to various cardiovascular diseases. Clinical studies have found that inflammation is involved in the entire process of atherosclerosis and plays a key role. Under normal physiological conditions, arterial vascular endothelial cells can resist the adhesion of white blood cells. However, due to various incentives such as eating a high saturated fat diet, smoking, high blood pressure, high blood sugar, obesity or insulin resistance, the anti-adhesion properties of vascular endothelial cells are reduced, allowing white blood cells to adhere to the arterial wall. In this process, vascular cell adhesion molecule-1 plays an important role. Vascular cell adhesion molecule-1 binds to monocytes and T lymphocytes to form early atherosclerotic plaques. Adherent monocytes can penetrate the endothelial lining into the inner membrane of the vessel wall. This is a process that requires monocyte chemoattractant protein-1 induction. It can recruit monocytes of the inflammatory type to characteristically accumulate white blood cells in early atherosclerosis. In the inner membrane, monocytes mature into macrophages and phagocytose modified lipoproteins, allowing cholesterol esters to aggregate in the cytoplasm. The final macrophage becomes foam cells, which are an early feature of atherosclerosis. At the same time, macrophages reproduce and release a variety of growth factors and cytokines, thereby maintaining and expanding the inflammatory signal. This process is regulated by macrophage colony stimulating factors. In addition, T lymphocytes, eosinophils, and mast cells are also induced by chemokines and enter the inflamed arterial wall.

Atherosclerosis has a long period of development, and it takes decades from the development of adolescent fatty streaks to complex plaques that cause cardiovascular disease in adults. IL-1β, IL-1α, TNF-α, and IL-6 expressed by vascular wall cells, as well as monocyte recruitment and activation of chemokines M-CSF, MCP-1, and IL-18 play an important role in vascular wall inflammation. In addition, another pro-inflammatory factor, CD40/CD154, is also involved in the development of atherosclerosis. Atherosclerosis caused by inflammation will destroy the fibrous cap on the vessel wall. The fibrous cap is an interstitial collagen with biomechanical strength and stability that acts to protect the blood from contacting with the accumulated lipid core. Inflammation destroys the fibrous cap by blocking the production of new collagen fibers and stimulating the destruction of existing collagen. Therefore, inflammation not only promotes the occurrence of atherosclerotic lesions and plaques, but also weakens the fibrous cap, causing the plaque to be easily broken and finally forming a thrombus.

Cardiovascular and Inflammation

The mechanism of inflammation in cardiovascular

In clinical studies, the presence of fatty streaks has been identified as one of the earliest stages of atherosclerosis. It can progress to fibrous plaques, and cause subsequent narrowing of the arterial lumen, ultimately leading to ischemia. Atherosclerotic plaques may also present with complications (unstable plaques) such as bleeding, ulcers, and thrombosis, resulting in a sudden occlusion of the artery and causing acute coronary syndrome (ACS). Atherosclerotic plaques have a unique microenvironment, which characterized are repeated inflammation and repair reactions that cause some mediator initiation and cell expansion. The work of Ross and colleagues describes key events in the development of atherosclerotic plaque, including the recruitment of macrophages by endothelial cells, proliferation of smooth muscle cells, and migration to the endothelial cell (EC) layer, and the participation of lymphocytes. Since the vascular endothelium is an important tissue secreted to regulate vasodilation and contraction factors, its dysfunction causes cardiovascular disease. In addition, increased production of reactive oxygen species (ROS) is also a feature of endothelial dysfunction. Because high levels of ROS cause LDLs in the vessel wall to be oxidized (ox-LDL), oxidized LDL induces proinflammatory factors expressed by endothelial cells, which promote foam cell formation and permanently endothelial dysfunction. The activated endoglin then expresses adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and selectin. They recruit monocyte cells to the vessel wall along with chemically inducible mediators such as complement factor, interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1). Monocytes differentiate into macrophages, which become foam cells through ox-LDL and release a variety of pro-inflammatory cytokines such as soluble CD40 ligands, IL-1, IL-3, IL-8 and IL-18, Tumor necrosis factor (TNF) alpha. In addition, the retention of lipoproteins in the vessel wall associated with the production of cholesterol crystals is another factor that exacerbates atherosclerosis. Induction of cell damage and apoptosis within the plaque further triggers and amplifies the release of the inflammatory response through the internal solubles of the dead cells. Cholesterol crystals are involved in the activation of the inflammatory body (the inflammatory body is a protein complex involved in the maturation and secretion of IL-1β), and the induction of vascular walls and lymphocytes to the intimal layer. The endothelium has accumulated low-density lipoproteins (LDLs), which are necessary events to trigger atherosclerotic lesions.

Clinical significance

It has now been clearly shown that atherosclerosis is a systemic disease, and clinical treatment can find its systemic therapy based on its inflammatory properties to instead of the reversal of arterial stenosis. Statins have clearly demonstrated their role as anti-atherosclerotic drugs, particularly their anti-inflammatory and immunomodulatory properties, which have been used as effective means of treating atherosclerosis and atherothrombotic thrombosis. In addition, several other possible therapeutic targets, including phospholipase A2, adhesion molecules, and even the immune system pathway, can be used as targets for the development of vaccines against atherosclerosis.

References:

  1. Peter Libby, Inflammation and cardiovascular disease mechanisms. Am J Clin. Nutr. 2006, 83: 456S–60S.
  2. Enrica Golia, et al. Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target. Curr Atheroscler Rep. 2014, 16:435.
  3. Libby P, et al. Inflammation and atherosclerosis. Circulation. 2002, 105(9):1135–43.
  4. Chatzizisis Y, et al. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007, 49: 2379-93.
  5. Schiro A, et al. Endothelial microparticles as conveyors of information in atherosclerotic disease. Atherosclerosis. 2014, 234: 295–302.

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