The Role of Chronic Inflammation in Cardiovascular Disease and its Regulation by Nutrients

Alternative Medicine Review, March, 2004 by Henry Osiecki

Abstract

Multiple risk markers for atherosclerosis and cardiovascular disease act in a synergistic way through inflammatory pathways. This article discusses some of the key inflammatory biochemical risk markers for cardiovascular disease; in particular, the role of three basic cell types affected by these risk markers (endothelial cells, smooth muscle cells, and immune cells), the crucial role of inflammatory mediators, nitric oxide balance in cardiovascular pathology, and the use of nutrients to circumvent several of these inflammatory pathways.

Most risk markers for cardiovascular disease have a pro-inflammatory component, which stimulates the release of a number of active molecules such as inflammatory mediators, reactive oxygen species, nitric oxide, and peroxynitrite from endothelial, vascular smooth muscle, and immune cells in response to injury. Nitric oxide plays a pivotal role in preventing the progression of atherosclerosis through its ability to induce vasodilation, suppress vascular smooth muscle proliferation, and reduce vascular lesion formation. Nutrients such as arginine, antioxidants (vitamins C and E, lipoic acid, glutathione), and enzyme cofactors (vitamins B2 and B3, folate, and tetrahydrobiopterin) help to elevate nitric oxide levels and may play an important role in the management of cardiovascular disease. Other dietary components such as DHA/EPA from fish oil, tocotrienols, vitamins B6 and B12, and quercetin contribute further to mitigating the inflammatory process.

Introduction

Multiple risk factors for atherosclerosis and cardiovascular disease include disordered lipid profiles, autoimmunity, infection, homocysteine, asymmetrical dimethylarginine. C-reactive protein, genetic predisposition, and various metabolic diseases. (1-5) Many risk factors act in a coordinated or synergistic way through one or two inflammatory pathways. Risk factors appear to act on three cell types that coordinate their action to influence cardiovascular dynamics, function, and structure. These cell types include:

* Endothelial cells that line the vascular lumen. They control the intra- and transcellular flow of nutrients, hormones, and immune cells, and regulate vascular tone and blood flow. (6)

* Smooth muscle cells (SMC) or vascular smooth muscle cells (VSMC) that maintain vascular tone and structure.

* Immune cells, including monocytes/ macrophages and T lymphocytes, which defend the endothelium and SMC from chemical and biological insult.

The disruption or over-expression of the coordinated activities of these cells can lead to cardiovascular disease. (7-10) Chronic inflammation is the most common disruptor of the activities of these cells. Risk factors for cardiovascular disease that have a pro-inflammatory component include LDL cholesterol, smoking, elevated blood sugar, hypertension, diabetes, infection, homocysteine, ischemia, oxidant damage, interleukin-6, lipoprotein (a), high sensitivity C-reactive protein (hs-CRP), serum intracellular adhesion molecule-1, and apolipoprotein-B. (2,4,5,11-14) In addition, these inflammatory risk markers can react synergistically to increase relative risk (Figure 1). One common link among these risk factors is the activity and metabolism of nitric oxide (NO).

[FIGURE 1 OMITTED]

Endothelial Cell Function

Endothelial cells play a vital physiological role in dividing blood from tissue. These cells actively inhibit the activation of the hemostatic mechanism and maintain blood circulation and fluidity, limit the efflux of cells and protein from the bloodstream, and participate in the maintenance of normal vasomotor tone. (6)

Endothelial cells are highly metabolically active and behave in a similar manner to paracrine or endocrine gland cells in the release of chemical mediators. (10,15,16) The endothelium generates a number of active molecules in response to injury or toxic chemical or oxidant stimuli, such as:

* Adhesion molecules, intracellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), fibronectin, selectins, interleukin-1, heparin sulfate (17)

* Clotting or coagulation factors (17,18) (von Willebrand Factor, thromboxane, prostacyclin)

* Fibrinolysis factors (19,20) (e.g., tissue plasminogen factor)

* Components of the renin-angiotensin system (21) (e.g., angiotensin II that acts as a pro-inflammatory cytokine and augments the production of reactive oxygen species)

* Prostaglandins (22-24) (e.g., prostacyclin)

* Growth-promoting or angiogenesis factors (transforming growth factor-beta (TGF-[beta]), platelet-derived growth factor (PDGF)) (25)

* Vascular tone regulators (18,25-28) (NO and endothelin-1)

These biological molecules demonstrate that the endothelium senses change in the local milieu, and respond by releasing a variety of cytokines and chemicals that regulate vascular smooth muscle relaxation/contraction, vascular structure, platelet and monocyte function, and coagulation. (26,28,31)

The endothelium secretes a number of vascular-relaxing substances as well as several vasoconstricting agents (Table 1). However, one of the most potent endogenous vasodilators is endothelial-derived nitric oxide. NO is a critical modulator of blood flow and blood pressure, (27,32) and opposes the vasoconstricting effects of endothelin, angiotensin II, serotonin, and norepinephrine. (31,33,34) NO also suppresses the proliferation of vascular smooth muscle. (28,35)