title: Protein kinase Cδ contributes to phenylephrine-mediated contraction in the aortae of high fat diet-induced obese mice.
abstract: The down-regulation of α-adrenoceptor-mediated signaling casacade has been implicated in obesity but the underlying mechanism remains largely unknown. The present study investigated whether inositol 1,4,5-trisphosphate (IP3) receptor and protein kinase C (PKC) were involved in the reduction of α1-adrenoceptor agonist phenylephrine-evoked contraction in aortae of high fat diet-induced obese (DIO) mice. C57BL/6 mice were fed with a rodent diet containing 45 kcal% fat for 16 weeks to induce obesity. Isolated mouse aortae were suspended in myograph for isometric force measurement. Protein phosphorylations and expressions were determined by Western blotting. In C57BL/6 mouse aortae, phenylephrine-induced contraction was partially inhibited by either IP3 receptor antagonist heparin or PKC inhibitor GFX, and the combined treatment with heparin and GFX abolished the contraction. Phenylephrine-induced contraction was significantly less in the aortae of DIO mice than those of control mice; only GFX but not heparin attenuated the contraction, indicating a diminishing role of IP3 receptor in DIO mice. Western blotting showed the reduced expression and phosphorylation of IP3 receptor and the down-regulated expression of PKC, PKCβ, PKCδ, and PKCζ in DIO mouse aortae. Importantly, PKCδ was more likely to maintain phenylephrine-mediated contraction in DIO mouse aortae because that (1) PKCδ inhibitor rottlerin but not PKCα and PKCβ inhibitor Gö6976, PKCβ inhibitor hispidin, or PKCζ pseudosubstrate inhibitor attenuated the contraction; and (2) PKCδ phosphorylation was increased but phosphorylations of PKCα, PKCβ, and PKCζ were reduced in DIO mouse aortae. The present study thus provides additional insights into the cellular mechanisms responsible for vascular dysfunction in obesity.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Peking, China. Electronic address: liu_limei@126.com.
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Peking, China.
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Peking, China.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Peking, China.
authors.forename: Dou
authors.initials: D
authors.lastname: Dou
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China. Electronic address: yu-huang@cuhk.edu.hk.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology*; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010656:Phenylephrine / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction; D014661:Vasoconstriction
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D010656:Phenylephrine; D051745:Protein Kinase C-delta
keywords: Aorta; Inositol 1,4,5-trisphosphate (IP3) receptor; Obesity; Protein kinase C; α-Adrenoceptor