page 517. Hermanowski-Vosatka and colleagues describe a novel chemical inhibitor that blocks the intracellular build up of the hormone cortisol, thereby preventing the development of atherosclerotic plaques in mice. This compound also alleviated multiple symptoms of a common disorder known as metabolic syndrome.As the epidemics of obesity and type 2 diabetes grow, so does the incidence of metabolic syndrome—a disorder characterized by hypertension, insulin resistance, and visceral obesity. These symptoms add up to an elevated risk of atherosclerosis and coronary heart disease.
Although the etiology of metabolic syndrome remains obscure, increased intracellular levels of the glucocorticoid cortisol may be partly to blame. Cortisol is an adrenal hormone that regulates nutrient metabolism and inflammation. Recent studies in mice showed that overexpression of 11β-HSD1—the intracellular enzyme that converts inactive cortisone into active cortisol—leads to a disorder resembling metabolic syndrome, suggesting that an excess of intracellular cortisol may contribute to disease.
Although cardiovascular disease is the leading cause of mortality among patients with metabolic syndrome, a role for 11β-HSD1 in the development of cardiovascular symptoms had never been explored. Hermanowski-Vosatka et al. now describe a novel inhibitor of 11β-HSD1 that reduced the accumulation of plaque-forming cholesterol by nearly 90% in the aortas of mice. This inhibitor also protected mice from diet-induced obesity and type 2 diabetes, suggesting that deregulation of intracellular cortisol may be a unifying cause of the symptoms of metabolic syndrome.
The dramatic protection against plaque formation was associated with only modest reductions in serum lipids and glucose (known contributors to atherosclerotic plaque formation), suggesting that the inhibitor also affects other pathways. The authors suspect that the drug may suppress inflammation in vessels, which could help protect against atherosclerosis, as inflammation is associated with exacerbated cardiovascular disease in both mice and humans.