Objective-There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor ␣ (PPAR␣) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPAR␣ activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells. Methods and Results-Bovine aortic endothelial cells were treated with the PPAR␣ activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPAR␣ action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment. Conclusions-PPAR␣ activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPAR␣-mediated cardiovascular protection. Key Words: atherosclerosis Ⅲ endothelium Ⅲ nitric oxide Ⅲ vascular biology Ⅲ vasodilatation H ypolipidemic fibrates are pharmacological compounds that activate peroxisome proliferator-activated receptor ␣ (PPAR␣), a member of the nuclear hormone receptor superfamily. 1 These fibrates have been widely used as effective drugs lowering serum triglycerides and low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol. 2 There has been accumulating evidence showing that fibrates have favorable effects of slowing the progression of atherosclerosis and reducing the number of events of coronary heart diseases in high-risk patients. 3-5 PPAR␣ is known to be expressed in the liver, which is mainly involved in lipid and lipoprotein metabolism exerted by fibrates. 1 In addition, recent studies have shown that PPAR␣ is also expressed in the cardiovascular system, including heart and vascular wall component cells such as vascular endothelial, vascular smooth muscle, and monocyte cells, and performs a direct antiatherogenic and antiinflammatory action. 6 Staels et al have shown that PPAR␣ ligands inhibit interleukin (IL)-1-induced expression of IL-6, prostaglandin, and cyclooxygenase 2 in aortic smooth muscle cells. 7 These authors further showed that patients receiving fenofibrate, a potent fibrate, had lower plasma C-reactive protein, fibrinogen, and IL-6 concentrations. 7 Furthermore, it has been demonstrated that PPAR␣ activators inhibit cytokine-induced vascular cell adhesion molecule-1 (VCAM-1), 8,9 and thrombin-induced endothelin-1 expression 10 in vascular en...

It has been known that the composition of the diet affects acid-base balance in the body. Remer et al. showed that high intake of protein-rich diet was metabolized to yield free sulfuric acid, which induced metabolic acidosis and urine acidification [1,2]. High dietary protein intake and the associated metabolic acidosis have been shown to adversely affect bone health in humans because of increased excretion of urinary calcium [3,4]. Likewise, an excessive protein intake could be associated with other pathological conditions.The metabolic syndrome is characterized by visceral obesity causing insulin resistance, elevated blood pressure, and dyslipidemia, which is a common basis of cardiovascular diseases [5]. Although the exact mechanism remains unclear, one possible explanation is that Abstract. Urine acidification is induced by metabolic acidosis which is associated with a high intake of protein-rich diet. The purpose of this study was to investigate the relationship of urine acidification with visceral obesity and the metabolic syndrome. We recruited 1,051 male subjects who underwent health examinations at the Health Care Center in Kinki Central Hospital. Subjects who were treated for hypertension, dyslipidemia, diabetes mellitus, and hyperuricemia and had the past history of chronic liver disease, chronic kidney disease and cancer, were excluded in this study. All subjects were administered to urine pH, blood and physical examinations. Lower urine pH was associated with higher serum urea nitrogen which reflects high intake of protein-rich diet, whereas it had no relation to serum creatinine. Lower urine pH was also associated with an increase in waist circumference, homeostasis model assessment-R, fasting plasma glucose, HbA1c, serum triglyceride, serum uric acid and with a decrease in high density lipoprotein cholesterol. Urine pH was not associated with mean blood pressure. Urine acidification is a characteristic of visceral obesity and the metabolic syndrome. High intake of protein-rich diet may contribute urine acidification, which is associated with various metabolic abnormalities in visceral obesity.Key words: Urine acidification, Metabolic acidosis, Metabolic syndrome, Hyperuricemia the increased cortisol production induces visceral obesity and insulin resistance [6], and thereby may promote the metabolic syndrome [7]. It is known that metabolic acidosis relates an increased cortisol production from adrenal glands. The epidemiologic study has established a close link between the elevated levels of serum uric acid and the increasing prevalence of the metabolic syndrome [8]. The elevated levels of serum uric acid are associated with increased cardiovascular morbidity and mortality in the US adult population [9]. These results suggested that hyperuricemia is one of components of the metabolic syndrome.The purpose of this study was to investigate the relationship of urine acidification with visceral obesity and the parameters of the metabolic syndrome in men. Materials and Methods SubjectsWe initially re...

Insulin and IGFs are potent inducers of skeletal muscle differentiation. Although PI3K is known to be involved in skeletal muscle differentiation, its downstream targets in this process are not clearly defined. We investigated the roles of Akt and mammalian target of rapamycin (mTOR) in skeletal muscle differentiation. LY294002, a pharmacological inhibitor of PI3K, and the immunosuppressant rapamycin inhibited insulin-induced differentiation of C2C12 myoblasts. LY294002 and rapamycin suppressed myosin heavy chain expression and myotube formation. Transient reporter assays showed that both inhibitors repress muscle creatine kinase (MCK) and myogenin gene transcription. Heterologous expression of Akt1/PKB(alpha) potently suppressed MCK gene transcription without affecting myogenin gene transcription, whereas heterologous expression of Akt2 increased myogenin and MCK gene transcription. Finally, overexpression of myogenin rescued the inhibitory effect of rapamycin on MCK gene transcription, whereas it failed to rescue the inhibitory effect of LY294002 and Akt1. These results suggest that insulin regulates myogenic differentiation chiefly at the level of myogenin gene transcription via PI3K and mTOR. PI3K activity, but not mTOR, may regulate transcriptional activity of myogenin. Our data also suggest that Akt1 and Akt2 play distinct roles in myogenic differentiation.

No abstract