title: The heme oxygenase system selectively modulates proteins implicated in metabolism, oxidative stress and inflammation in spontaneously hypertensive rats.
abstract: Although recent studies have underscored the role of the heme-oxygenase (HO) inducer hemin, on insulin-signaling and glucose metabolism, the underlying mechanisms are not completely understood. In this study, two-dimensional-gel electrophoresis, massspectrometry and MSACOT-analyses were used to identify and characterize novel proteins modulated by hemin in spontaneoushypertensive rat (SHR), a model of essential hypertension with insulin resistance/impaired glucose metabolism. In addition, the effects of hemin on endothelin-1 (ET-1), protein-tyrosine-phosphatase-1B (PTP-1B), atrial-natriuretic-peptide (ANP) and its surrogate-marker urinary cGMP, and inflammatory cytokines including TNF-α, IL-6 and IL-1β were investigated. In hemin-treated SHR, several proteins related to oxidative-stress and metabolism were modulated. Particularly, hemin enhanced aldolase- B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase and carbonic anhydrase-3 all of which are enzymes involved in glucose/energy metabolism and pH homeostasis. Similarly, hemin potentiated antioxidant pathways including, NADP(+)-dependant isocitrate-dehydrogenase, catalase, glutathione-S-transferase-Yb1 and hsp70, a pleiotropic agent that regulates protein-folding, oxidative/pro-inflammatory events. Hemin also increased enzymes implicated in cell-growth such as the nitrilase-protein-family, but reduced betaine-homocysteine methyltransferase, an enzyme associated with insulin resistance and dysfunctional glucose metabolism. Furthermore, hemin increased ANP and its surrogate marker, urinary cGMP, but reduced ET-1, PTP-1B, TNF-α, IL-6, IL-1β, whereas the HO-inhibitor, chromium-mesoporphyrin abolished the effects. The potentiation of ANP, urinary-cGMP, aldolade-B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase, carbonic anhydrase-3, hsp70 and the corresponding reduction of betaine-homocysteine methyltransferase, PTP-1B, TNF-α, IL-6, IL-1β, and ET-1 may be responsible for the improved glucose metabolism in hemin-treated animals. Collectively, these findings underscore the pleiotropic effects of the HO-system in cellular homeostasis with important roles in metabolism and defence.
authors: Department of Physiology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5. joseph.ndisang@usask.ca.
authors: Joseph Fomusi
authors: JF
authors: Ndisang
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D019332:Endothelin-1 / Q000378:metabolism; D000075222:Essential Hypertension; D005260:Female; D005947:Glucose / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006427:Hemin / Q000008:administration & dosage; D006973:Hypertension / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D013058:Mass Spectrometry; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D019332:Endothelin-1; D018836:Inflammation Mediators; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D006152:Cyclic GMP; D005947:Glucose