ADAM17 and Caveolin-1 in Cardiac Syndrome X

Cardiac syndrome X has the standard risk factors for cardiovascular disease, which is to say age of the individual and degree of excess fat tissue carried by the individual. It is a comparatively poorly understood variety of structural alteration and failure of blood vessels, however. The risk factors are well known, but the biochemistry is yet to be mapped in full. Here, researchers shed more light onto what is taking place under the hood.

"Older obese patients and sometimes women who suffer heart failure go to the cardiac catheterization lab and the cardiologist finds nothing that would explain their heart failure. They have normal large blood vessels in the heart still the heart failure has developed." What isn't readily seen with these routine exams is the thickened walls that can hinder dilation of the small capillaries fed by these bigger vessels, a condition called coronary microvascular dysfunction, or cardiac syndrome X.

In patients and animal models, who are both older and obese, researchers have found a key dynamic in the dysfunction is an enzyme called ADAM17, which is involved in a huge variety of functions like releasing growth factors as we develop, but also implicated in diseases from Alzheimer's to arthritis. ADAM17 levels increase in obesity while levels of its natural inhibitor, the protein caveolin-1, decrease with age, enabling the perfect storm. ADAM17 was discovered 20 years ago for its ability to cut and release previously inactive tumor necrosis factor, or TNF, from the cell membrane. TNF is a major promoter of inflammation that also directly impacts the function of the endothelial cells that line blood vessels. The scientist found that ADAM17 cleaves TNF from fat, releasing it into the bloodstream where it preferentially targets the heart. The bottom line: the walls of the hair-sized microvasculature become thicker, less elastic, less able to dilate and to properly sustain the heart.

The research team found ADAM17 highly expressed in fat and even higher in the blood vessels of aged human fat. The protein level was increased in younger mice on a high-fat diet, but the significant increase in its activity came with age and fat. In humans, they saw the ability of the tiny vessels to dilate significantly reduced in those ages 69 and older and further reduced in older individuals - males and females - who also were obese. They found ADAM17 present in the fat of young and old mice on high-fat diets compared to normals, but it was only significantly active in the older mice on a high-fat diet. When they looked at younger and older obese patients, again much like the mice, they found high levels of expression of ADAM17 in the lining of blood vessel walls. When they transplanted fat from aged obese mice to younger mice, it increased circulating levels of proinflammatory factors and impaired dilation of the coronary microvasculature. "It basically mimicked the old vascular phenotype in the young animals."

The researchers have started to look at antibodies that would directly target and ideally reduce levels of ADAM17 in the face of aged fat and at least delay development of small vessel disease. They further think a similar process may happen in the brains of older obese individuals, so have ongoing studies of how microvascular disease can lead to Alzheimer's in these individuals. The researchers note that young, obese individuals could help themselves avoid this and likely other diseases like diabetes, by losing weight while they are young.

Link: http://jagwire.augusta.edu/archives/45733

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