Inhibition and regression of atherosclerotic lesions

Abstract

Atherosclerosis, once believed to be a result of a slow, irreversible process resulting from lipid accumulation in arterial walls, is now recognized as a dynamic process with reversibility. Liver-directed gene therapy for dyslipidemia aims to treat patients who are not responsive to currently available primary and secondary prevention. Moreover, gene therapy strategies have also proved valuable in studying the dynamics of atherosclerotic lesion formation, progression, and remodeling in experimental animals. Recent results on the long-term effect of gene therapy suggest that hepatic expression of therapeutic genes suppresses inflammation and has profound effects on the nature of the atherogenic process.

Figure 1. Development of atherosclerosis.

Monocytes and T-leukocytes do not adhere to ECs under normal conditions. 1. Adhesion. When ECs undergo inflammatory activation they express adhesion molecules, and leukocytes are trapped by ECs. 2. Transmigration. Once adherent, leukocytes migrate into the intima. 3. Foam cell formation. In the intima, monocytes differentiate into macrophages and take up lipids. 4. Progression. T cells are activated and further stimulate macrophages. SMCs of the media migrate to the top of the intima to form a fibrous cap over the lipid core. Further activation of macrophages produces MMPs that degrade the extracellular matrix and weaken the fibrous cap. 5. Plaque rupture. When the plaque ruptures, it allows the blood to contact to the procoagulant protein, tissue factor, and activate the coagulant cascade. Macrophages eventually die in a central core by apoptosis or necrosis, which forms a necrotic core in the lesion. IFN-γ, interferon-γ; MCP-1, monocyte chemoattractant protein-1; mLDL, modified LDL; MMP, matrix metalloproteinase; SR, scavenger receptors; TF, tissue factor. Note: Mast cells play an important role in atherogenesis. The interaction of the chemokine receptor CCR3 on the surface of mast cells and eotaxin, a chemoattractant, may facilitate the trans-migration of these cells. In the intima, they undergo degranulation and release factors that contribute to atherogenesis. Mast cells are not indicated.

Figure 2. Evolution of atheroma.

The normal human coronary artery has a trilaminar structure. 1. Early atherosclerotic lesions. In early atherogenesis, migration of immune cells and the accumulation of lipids in macrophages lead to the formation of fatty streaks. These early lesions frequently regress spontaneously. 2. Vulnerable plaque. If inflammatory conditions persist, the lipid core grows. Further activation of macrophages secretes matrix degrading enzymes and weakens the fibrous cap, which leads to vulnerable plaques prone to rupture. 3. Plaque rupture. Disruption of the fibrous cap causes the direct contact of blood components to tissue factor and initiates coagulation. This leads to the formation of the thrombus. 4. Stenosis. A wound healing response stimulates smooth muscle cell migration and collagen synthesis. This process results in a thick fibrous cap and expansion of the intima, which constricts the lumen. 5. Stabilization. Drug treatment or gene therapy for dyslipidemia remodels the nature of the vulnerable plaques, which reduces the incidence of acute coronary events. 6. Regression. Advanced atherosclerotic lesions could be regressed under aggressive lipid lowering or drug treatments.