Activation of Coronary Arteriolar PKCβ2 Impairs Endothelial NO-Mediated Vasodilation: Role of JNK/Rho Kinase Signaling and Xanthine Oxidase Activation.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Vasodilation*/genetics; Coronary Vessels/*metabolism ; Endothelium, Vascular/*metabolism ; Nitric Oxide/*metabolism ; Protein Kinase C beta/*metabolism; Animals ; Immunohistochemistry ; NADPH Oxidases/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Phorbol 12,13-Dibutyrate/pharmacology ; Protein Kinase C beta/genetics ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; Swine ; Vasodilator Agents/pharmacology ; Xanthine Oxidase/metabolism

Protein kinase C (PKC) activation can evoke vasoconstriction and contribute to coronary disease. However, it is unclear whether PKC activation, without activating the contractile machinery, can lead to coronary arteriolar dysfunction. The vasoconstriction induced by the PKC activator phorbol 12,13-dibutyrate (PDBu) was examined in isolated porcine coronary arterioles. The PDBu-evoked vasoconstriction was sensitive to a broad-spectrum PKC inhibitor but not affected by inhibiting PKCβ2 or Rho kinase. After exposure of the vessels to a sub-vasomotor concentration of PDBu (1 nmol/L, 60 min), the endothelium-dependent nitric oxide (NO)-mediated dilations in response to serotonin and adenosine were compromised but the dilation induced by the NO donor sodium nitroprusside was unaltered. PDBu elevated superoxide production, which was blocked by the superoxide scavenger Tempol. The impaired NO-mediated vasodilations were reversed by Tempol or inhibition of PKCβ2, xanthine oxidase, c-Jun N-terminal kinase (JNK) and Rho kinase but were not affected by a hydrogen peroxide scavenger or inhibitors of NAD(P)H oxidase and p38 kinase. The PKCβ2 protein was detected in the arteriolar wall and co-localized with endothelial NO synthase. In conclusion, activation of PKCβ2 appears to compromise NO-mediated vasodilation via Rho kinase-mediated JNK signaling and superoxide production from xanthine oxidase, independent of the activation of the smooth muscle contractile machinery.

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R01EY018420 Office of Extramural Research, National Institutes of Health; Kruse Chair Fund Baylor Scott and White Health

Keywords: coronary disease; nitric oxide; oxidative stress; phorbol esters; superoxide; vasoconstriction; vasodilation

0 (Reactive Oxygen Species)
0 (Vasodilator Agents)
11062-77-4 (Superoxides)
31C4KY9ESH (Nitric Oxide)
37558-16-0 (Phorbol 12,13-Dibutyrate)
EC 1.14.13.39 (Nitric Oxide Synthase Type III)
EC 1.17.3.2 (Xanthine Oxidase)
EC 1.6.3.- (NADPH Oxidases)
EC 2.7.11.13 (Protein Kinase C beta)

Date Created: 20210928 Date Completed: 20211101 Latest Revision: 20211101

20240829

PMC8471475

10.3390/ijms22189763

34575925