Study explains how low blood flow promotes vascular disease

Washington, June24 : In a rodent study on circulation, researchers have found evidence that a key protein, called cyclophilin A, leads to clogging of arteries in two ways, and that lowering levels of it opens them up.

The findings indicate that cyclophilin A can act as an exciting target in the design of drugs against atherosclerosis, the number one cause of heart attacks and strokes, which occur when vessels become completely blocked.

The current study unites three major discoveries in cardiovascular science in the last 20 years by providing strong evidence that cyclophilin A, a protein involved in the immune response, has dual roles in vascular disease.

Cyclophilin A recruits immune cells that cause inflammation, and it drives pathogenic growth and remodeling, when triggered by reactive oxygen species in diseased blood vessels.

"For years researchers worldwide have sought to determine exactly how low blood flow and the immune reaction to cholesterol deposits, along with the reactive oxygen species created by both, drive the progression of atherosclerosis. We are tremendously excited by these results because they provide solid evidence that cyclophilin A is at the center of it all," said Bradford C. Berk, M.D., Ph.D., professor of Medicine in the Aab Cardiovascular Research Institute within the University of Rochester Medical Center, and senior author of the study.

In the study, Berk's team genetically engineered one group of mice to produce less CyPA, another group to make more, and compared both groups to "normal" mice as all three groups experienced reduced blood flow in the carotid artery.

Reduced blood flow increased CyPA expression in the vascular wall, and promoted the migration of smooth muscle cells into the intima, where they began to grow (proliferate) and contribute to the formation of atherosclerotic lesions. Reduced flow, and the related increase in CyPA signaling, also caused the accumulation of inflammatory cells, an important component in the disease-related thickening of vessel walls. The effects were pronounced in the mice with extra capacity for CyPA production, and lessened in those with less CyPA.

The study, showed for the first time that in a live animal that cyclophilin A (CyPA) is secreted specifically by smooth muscle cells in response to the production of reactive oxygen species with several consequences.

First, CyPA signals for the production of pro-inflammatory molecules like E-selectin and vascular cell adhesion molecule 1 (VCAM-1), both of which call in immune cells circulating in the blood to the site of a cholesterol deposit in blood vessel wall and enable them to stick to it. This represents a first step in the inflammatory component of plaque formation.

The researchers also showed that CyPA stimulates important pathways (e.g. the ERK1/2 and JAK/STAT) that drive smooth muscle cells to divide and grow.

Also, CyPA may activate matrix metalloproteinases, enzymes that break down the barrier that usually keeps smooth muscle cells out of the intima, the site of their disease-related proliferation.

The study results are published in the latest edition of the journal Circulation.

ANI