Is low-heat shock protein 70 a primary or a secondary event in the development of atherosclerosis?

Is Low-Heat Shock Protein 70 a Primary or a Secondary Event in the Development of Atherosclerosis? Letter to the Editor: Pockley et al’s landmark observation that serum heat shock protein (Hsp) 70 levels predict the development of atherosclerosis1 prompts the question whether Hsp 70 is low as a result of atherosclerosis or the primary event leading to atherosclerosis. We believe an argument can be made for either a primary or a secondary event, or even a combination of both. First, low Hsp 70, itself, should add to the vulnerability of the artery to stress because, indeed, Hsp 70 protects cellular elements from injury by reducing oxidation, inflammation, and apoptosis and by refolding damaged proteins.2 As a secondary event, Hsp 70 may be low as a result of decreased release of nitric oxide into the circulation caused by endothelial dysfunction. Nitric oxide normally has an oxidizing effect that increases Hsp 70 expression, additionally, studies show that blocking nitric oxide release reduces Hsp expression.3 Thus, low levels of Hsp 70 in subjects with progressive atherosclerosis could be the result of primary endothelial dysfunction. However, reduced Hsp 70 may be a primary event in the development of atherosclerosis. Hsp 70 recently has been found to be markedly low in the skeletal muscle of individuals with type 2 diabetes and moderately low in the nondiabetic identical twin with a diabetic co-twin.4,5 Furthermore, in a study comparing 5600 genes of nondiabetic subjects with insulin-resistant diabetic subjects, Hsp 70 was one of only 17 genes that were significantly lower in individuals with diabetes.6 These studies suggest that reduced Hsp 70 may be a necessary event leading to the development of diabetes and subsequent atherosclerosis.