Essential role of PKC-ζ in normal and angiotensin II-accelerated neointimal growth after vascular injury

Abstract

The contribution of atypical protein kinase C (PKC)-zeta to ANG II-accelerated restenosis after endoluminal vascular injury was investigated by using the rat carotid balloon injury model. Exposure of injured arteries to ANG II resulted in an extensive neointimal thickening (1.9 times) compared with vehicle at day 14. Treatment with PKC-zeta antisense, but not scrambled, oligonucleotides reduced neointimal formation observed in the presence or absence of ANG II. Examination of early events (2 days) after injury showed an increase in cellularity in the perivascular area of the artery wall that was transferred to the adventitia and media after exposure to ANG II, events blocked by PKC-zeta antisense, but not scrambled, oligonucleotides. A positive correlation between medial cellularity at day 2 and extent of neointimal growth at day 14 was established. Immunohistochemical analysis showed that upregulation of inflammatory markers after injury, as well as infiltration of ED1(+) monocytes/macrophages from the perivascular area to the adventitia, was accelerated by ANG II. However, ANG II-stimulated medial increase in cellularity was proliferation independent, and these cells were monocyte chemoattractant protein-1(+)/vimentin(+) but ED1(-)/VCAM(-). PKC-zeta is degraded after injury, and inhibition of its neosynthesis in medial vascular smooth muscle cells or in infiltrating cells with PKC-zeta antisense attenuated medial cellularity and expression of inflammation mediators without reversing smooth muscle cell dedifferentiation. Together, these data indicate that PKC-zeta plays a critical role in normal and ANG II-accelerated neointimal growth through a mechanism involving upregulation of inflammatory mediators, leading to cell infiltration in the media of the vascular wall.

Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

“…Consistent with the notion that PKC is a novel G␣ q effector, agonists acting through G q -coupled GPCR such as angiotensin II, phenylephrine, platelet-activating-factor, or thromboxane A2 have been shown to promote PKC translocation and activation in several cell types (24 -26, 32, 33), and PKC has been suggested to participate in GPCR-mediated control of cell proliferation (25)(26)(27), eosinophil degranulation (32), or smooth muscle cell adhesion, spreading, and hypertrophy (25). Several authors have suggested a role for PKC in ERK1/2 activation by GPCR (34,35), although another recent report indicates that inhibition of PKC in adult cardiomyocytes has no effect in ERK1/2 activation by G q -coupled GPCR (36).…”

Angiotensin-Converting Enzyme and Vascular Remodeling

“…Inhibition of protein kinase C-attenuated medial cellularity and expression of inflammatory mediators. 29 ACE inhibitors have been shown to inhibit neointima formation in response to vascular injury in several models and species, such as in balloon-induced vascular injury in rats 30 and guinea pig, 31 in allograft-induced intima formation in rats, 32 and cuff-induced neointima formation in mice. 24,33 Several follow-up studies in these models showed that the favorable effects of ACE inhibition could be attributed, in part, to the bradykinin/endothelial NO synthase pathway and/or oxidative stress/NAD(P)H pathway.…”

Oxidative Stress in Mononuclear Cells Plays a Dominant Role in Their Adhesion to Mouse Femoral Artery After Injury

“…1,2 Angiotensin (Ang) II is known to induce oxidative stress and leukocyte adhesion in the vascular wall, 3,4 whereas the local renin-angiotensin system in the vasculature plays an important role in the development of injury-induced inflammation. 5,6 Recent studies suggest an efficacy of Ang II type 1 receptor blocker (ARB) in reducing intimal hyperplasia after mechanical injury in animal models. 7,8 However, the role of ARB in the modulation of vascular inflammation at the early phase of the injury has not been fully investigated.…”