Matrix metalloproteinase inhibition with tetracyclines for the treatment of coronary artery disease.

Coronary artery disease is caused by atherosclerosis - a progressive arterial inflammatory disease that is responsible for significant global mortality and morbidity through the development of the acute coronary syndromes: sudden cardiac death, acute myocardial infarction and unstable angina. These clinical entities share a common pathophysiology: rupture of atherosclerotic plaque resulting in abrupt complete or partial thrombotic obstruction of coronary blood flow. Matrix metalloproteinases (MMP), through their central role in tissue remodeling and inflammation, are secreted by inflammatory cells of the atherosclerotic plaque and are capable of degrading all the extracellular matrix components of the fibrous cap that separates the atherosclerotic lesion from blood flow in the arterial lumen. Plaque rupture occurs when the circumferential tensile stresses in the artery overwhelm the structural integrity of the progressively degraded, thinned and weakened fibrous cap of the atherosclerotic lesion. Tetracyclines inhibit MMPs through their ability to chelate zinc. Subantimicrobial doses of doxycycline have been shown to reduce inflammation and inhibit MMP activity in patients with coronary artery disease. Further investigation is warranted to assess the potential clinical risks and benefits of MMP inhibition with tetracyclines or other agents in the treatment of coronary artery disease.