Arterial stiffening has long been considered a major risk factor for cardiovascular disease. Keeping arteries soft and supple might reduce disease risk, but the mechanisms of how arteries stave off hardening has remained elusive.
Researchers from the Perelman School of Medicine, University of Pennsylvania, Wistar Institute, and The Children's Hospital of Philadelphia have discovered that the protein apolipoprotein E (apoE) plays a major role in maintaining arterial softness by suppressing production of the extracellular matrix, a network of connective tissue in the body. Their research appeared in the most recent issue of Cell Reports.
ApoE is a component of several lipoproteins, including HDL, the "good" cholesterol, and is generally believed to forestall atherosclerosis. But several recent major studies have questioned the link between HDL and cardiovascular protection. Meanwhile, other research involving cultured cells has indicated that apoE has effects beyond its role in regulating lipid levels as a component of HDL. The present work suggests that it may be the apoE-containing HDL that confers the main benefit of HDL by promoting arterial softness.
Analyzing genetic datasets of regular mice and mutant mice without apoE, the researchers showed definite differences in gene expression, with the apoE-null mice displaying marked increase in indicators of stiffening - the proteins collagen, fibronectin, and lysyl oxidase in response to stiffening in the aorta, which led to severe atherosclerosis. To attempt to mitigate the atherosclerosis seen in the apoE-null mice, the researchers fed them a high-fat diet and treated them with a lysyl oxidase inhibitor, which softened their arteries.
Despite highly elevated cholesterol, the mice showed a marked improvement in their atherosclerosis. The results suggest that the lack of apoE results in arterial stiffness, and that even with high cholesterol, increasing arterial elasticity by pharmacologic means can greatly reduce atherosclerotic disease.
"HDL can't be looked at as just one compound, because it is a mixture of different molecular components," explains senior author Richard K. Assoian, PhD, professor of Pharmacology. "The component that has these effects on arterial stiffening is a minor part of total HDL." Assoian notes that this could help to reconcile the conflicting clinical evidence regarding the link between HDL and reduced cardiovascular disease. "It might be the apoE HDL fraction that you need to keep high and not worry about the total HDL," he suggests. Because apoE is only about 6 percent of total HDL, "it could go up sky high or not at all, and you probably wouldn't detect it in these studies that try to raise total HDL."