Drug Discovery Opinion

Both high blood pressure and atherosclerosis, a condition in which the arteries become narrowed by atheroma, are major risk factors for cardiovascular diseases, including heart attack and stroke. The atheromatous plaques are made up of cells (mostly macrophages) or cell debris containing oxidised lipids, calcium and connective tissue.

A team led by scientists in the UK has now shown that matrix metalloproteinase-8 (MMP8) plays a crucial role both in raising blood pressure, and in causing the abnormal build-up of cells and fatty deposits in the arteries. MMPs are best known for their ability to degrade extracellular matrix proteins such as collagen, but have also been shown to cleave a variety of other proteins. As well as degrading collagen type 1, MMP8 has been shown to cleave angiotensin I to produce the vasopressor, angiotensin II. This conversion is also carried out by angiotensin converting enzyme (ACE) and ACE inhibitors are commonly prescribed to treat patients with high blood pressure and congestive heart failure as well as those who have suffered a heart attack. In the present study, the team found that inactivating MMP8 in apolipoprotein E-deficient mice – which are prone to atherosclerosis – resulted in a substantial reduction in atherosclerotic lesions and that the lesions had fewer macrophages but increased collagen content. The knockout mice were also found to have reduced levels of angiotensin II and lower blood pressure, as well as reduced expression of vascular cell adhesion molecule (VCAM)-1 in atherosclerotic lesions.

The team also evaluated data from a group of 2000 patients with coronary artery disease who were undergoing a coronary angiogram procedure and found an association between an MMP8 gene variant and degree of atherosclerosis. The researchers hope that their findings will lead to new drugs to treat hypertension and prevent heart disease, particularly for patients who fail to respond well to ACE inhibitors.

The study is published in the journal Circulation Research.

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