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Circadian Clock in Angiotensin II Induced Hypertension and Vascular DiseaseHypertension remains a major risk factor for cardiovascular disease and death. While clinical studies and guideline recommendations underscore the benefits of reducing sodium intake in the treatment of high blood pressure, recent human data suggest that underlying conditions of disease may confound these positive effects of low salt diets. Herein, we examined the influence of circadian dysfunction during experimental hypertension caused by angiotensin II (Ang II), a key peptide in blood pressure regulation. While a low salt diet caused the expected decrease in blood pressure in wild type (WT) mice, mice with disruption of the circadian clock exhibited a paradoxical response to low salt. Mice with disruption in the circadian clock component Period (Period-knockout/KO mice), were abolished in blood pressure rhythm due to an increase in daytime blood pressure. This impairment in blood pressure rhythm in Per-KO mice on the low salt diet was restored to rhythmic oscillation by the angiotensin receptor blocker losartan. Similarly, exogenous administration of Ang Il caused a non-dipping blood pressure phenotype in the Per-KO mice on a normal salt diet, which resulted in pathological thickening of the vasculature indicative of vascular disease. These effects were related to circadian rhythm as impairment in blood pressure caused by low salt was recapitulated in WT mice induced to circadian derangement by a shortened light cycle. Further thickening of the vasculature and increased renin levels were observed in Per-KO mice on a chronic low salt diet but not in WT mice. Moreover, disruption of the Period gene altered ATI receptor expression and other components of the renin-angiotensin system. These data suggest that circadian dysfunction may compromise the benefits of a low salt diet and support recent clinical data that raise caution to sodium restriction as a therapy for hypertension.
Increasing Muscle Mass by Deletion of Myostatin Improves Metabolic and Vascular Function in Obese (db/db) MiceObesity is the major emerging risk factor in the disease burden of western cultures. Obesity significantly reduces both metabolic and cardiovascular function, most notably inducing a state of insulin resistance in the former case and impeding endothelial control of vascular function in the latter. Mechanisms underpinning these defects are poorly understood and interventional therapies remain few. Exercise is a powerful method to limit or improve obesity-associated diseases, improving metabolic syndrome markers and endothelial function in obese patients. The salutatory effects of exercise are multi-factorial and include increases in muscle size and quality, reduction in fat mass and alterations in the components of plasma milieu. The relationships between the physiologic changes induced by exercise and improvements in metabolic and cardiovascular function are poorly defined. Myostatin, a TGF-β family member, is secreted by muscle, limits muscle growth and stimulates adipose tissue accumulation. Thus deletion of myostatin permits a method of assessing whether a component of exercise, increases in muscle mass, has positive effects on metabolic and vascular function. While myostatin deletion can improve glucose tolerance, the mechanisms are unclear. Whether myostatin deletion improves endothelial function in obesity is also not clear. The overall goal of the current study was to determine if increasing muscle mass by deletion of myostatin improves metabolic and vascular function in obese (db/db) mice.