Free radicals, particularly reactive oxygen species (ROS), play a crucial role in the initiation, progression, and complications of atherosclerosis, a key underlying cause of cardiovascular diseases such as coronary artery disease, stroke, and peripheral arterial disease.
Atherosclerosis is characterized by the accumulation of lipids, inflammatory cells, and fibrous elements in the large arteries, leading to plaque formation, arterial stiffness, and eventually, reduced blood flow.
Initiation of Atherosclerosis
1. Oxidation of LDL:
The oxidative modification hypothesis suggests that low-density lipoprotein (LDL) must be oxidatively modified before it can contribute to atherogenesis.
ROS can oxidize LDL, transforming it into oxidized LDL (oxLDL), which is more atherogenic.
OxLDL is readily taken up by macrophages through scavenger receptors, leading to the formation of foam cells, a hallmark of early atherosclerotic plaques.
2. Endothelial Dysfunction:
ROS contribute to endothelial dysfunction, an early event in atherosclerosis, by reducing the bioavailability of nitric oxide (NO), an important vasodilator and anti-inflammatory molecule.
Decreased NO levels lead to increased endothelial permeability, enhanced leukocyte adhesion, and vascular inflammation, facilitating the development of atherosclerotic lesions.
Progression of Atherosclerosis
1. Inflammatory Response:
ROS stimulate the expression of pro-inflammatory cytokines and adhesion molecules in endothelial cells, promoting the recruitment and migration of inflammatory cells (e.g., monocytes and T-lymphocytes) into the arterial wall.
This inflammation is central to the progression of atherosclerotic plaques.
2. Smooth Muscle Cell Proliferation:
Oxidative stress can also induce the proliferation and migration of vascular smooth muscle cells (VSMCs) from the media to the intima layer of the artery, where they contribute to plaque growth and fibrous cap formation, further narrowing the artery.
Complications of Atherosclerosis
1. Plaque Instability and Rupture:
ROS are implicated in the destabilization of atherosclerotic plaques.
Oxidative stress can degrade collagen and other extracellular matrix components in the fibrous cap, weakening it.
A weak cap is prone to rupture, which can lead to thrombus formation and acute cardiovascular events like myocardial infarction and stroke.
2. Thrombosis:
Following plaque rupture, ROS can further contribute to thrombosis by activating platelets and the coagulation cascade, leading to clot formation that can acutely block blood flow.
Therapeutic Implications:
Antioxidants have been studied as potential therapeutic agents to combat atherosclerosis by neutralizing free radicals and reducing oxidative stress.
While some antioxidant supplements have shown limited efficacy in clinical trials, maintaining a diet rich in natural antioxidants (found in fruits, vegetables, and whole grains) and adopting a healthy lifestyle (including exercise) can help reduce oxidative stress and the risk of atherosclerosis.