• Increasing Muscle Mass by Deletion of Myostatin Improves Metabolic and Vascular Function in Obese (db/db) Mice

      Qiu, Shuiqing; Department of Biochemistry and Molecular Biology (2014)
      Obesity 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.
    • Role of Oxidative Stress in High Endothelin Models of Hypertension

      Elmarakby, Ahmed A.; Department of Medicine (2004-07)
      Recent studies have shown that the potent vasoconstrictor peptide endothelin-1 (ET-1) stimulates superoxide production in vivo and in vitro. We hypothesized that ET-1 induced hypertension, at least in part, is due to an increase in oxidative stress. In the initial experiments, we hypothesized that ETA receptor stimulation contributes to the elevated blood pressure and superoxide production in ETB receptor deficient rats as an example of a high endothelin model of hypertension. Experiments were conducted on homozygous {si/si) ETB deficient and wild type {wt) rats fed a high salt diet for three weeks. Separate groups of rats were given normal drinking water or water containing the ETA receptor antagonist, ABT 627. On a normal salt diet, sl/sl rats had a significantly elevated systolic blood pressure (SBP) compared to wt. High salt caused a significant increase in SBP in sl/sl compared with wt rats. ETA receptor blockade decreased SBP in sl/sl rats on high salt without affecting the blood pressure in wt rats. Plasma 8-isoprostane levels, an indirect measure of oxidative stress, were significantly higher in sl/sl rats compared with the wt. ETa receptor blockade significantly attenuated the elevation in plasma 8- isoprostane levels in sl/sl rats'. These findings suggest that ET-1, through the ETA receptor, contributes to salt-induced hypertension and superoxide production in ETB deficient rats. We hypothesized that ET-1 increases superoxide production via the stimulation of the NADPH oxidase system. Chronic ET-1 infused rats were fed a high salt diet and either allowed to drink tap water, water containing the SOD mimetic, tempol, or the NADPH oxidase inhibitor, apocynin, for two weeks. Infusion of ET-1 increased mean arterial pressure (MAP) when compared to baseline values. Neither tempol nor apocynin treatment had any effect on the increase in MAP produced by ET 1. Plasma 8-isoprostane was increased significantly in ET-1 infused rats compared to rats on a high salt diet alone. Both tempol and apocynin treatment significantly attenuated the ET-1 induced increase in plasma 8-isoprostane. These data provide evidence that chronic ET-1 infusion increases vascular NADPH oxidase dependent superoxide production, but does not account for chronic ET-1-induced hypertension. Finally, experiments were performed to determine if increased kinins and/or decreased superoxide attenuates the elevation in blood pressure in chronic Ang II hypertensive rats. Four groups of rats, all given Ang II, were studied and allowed to drink tap water, water containing enalapril, tempol, or both for two weeks. Ang II infusion significantly increased SBP when compared with the baseline. Neither enalapril nor tempol treatment alone was able to attenuate the elevation in SBP. Combined administration of tempol and enalapril prevented the increase in SBP. Plasma 8-isoprostane was elevated significantly in Ang II infused rats when compared with control untreated rats. Tempol treatment alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane. These studies support the hypothesis that an antioxidant alone is not effective in preventing Ang II hypertension. However, administration of an ACE inhibitor with an antioxidant enhances antioxidant efficiency in preventing Ang II hypertension. Overall, these studies showed that ETA receptor stimulation participates in superoxide production via the stimulation of NADPH oxidase and that antioxidant treatment alone is not sufficient to lower blood pressure in high endothelin models of hypertension.