Cardiovascular Research Advance Access originally published online on April 8, 2008
Cardiovascular Research 2008 78(3):409-410; doi:10.1093/cvr/cvn089
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Pulmonary hyperplasia and the two sides of PKC
Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany
* Corresponding author. Tel: +49 30 4593 2413; fax: +49 30 4593 2415. E-mail address: graf{at}dhzb.de
Protein kinase C (PKC) was initially identified by Nishizuka and coworkers1 as a nucleotide-independent, Ca2+-dependent serine kinase. Molecular cloning identified at least 11 isozymes of PKC that were further divided into subfamilies based on sequence homology and mode of stimulation. The classical PKCs (
, βI, βII, and 
) are diacylglycerol (DAG) and calcium-dependent enzymes, whereas the novel PKCs (
, 
, 
, and 
) require DAG, but not calcium, for activation. The atypical PKCs (
, 
/
) are not responsive to activation by DAG or calcium, but are activated by other lipid-derived second messengers. PKCs contain N-terminal regulatory and C-terminal catalytic domains separated by a flexible hinge region. In the absence of activating cofactors, the catalytic domain is subject to autoinhibition by the regulatory domain that is mediated, in part, by a pseudosubstrate sequence motif resembling the consensus sequence for phosphorylation by PKC.2 PKCs in general are involved in multiple intracellular mechanisms, and although they belong to one family they might contribute to opposing effects by activating intracellularly various pathways.
In cardiovascular diseases, PKCs play a prominent role in promoting pathophysiological effects. PKC , β, , , and have been shown to be involved in proatherosclerotic effects in vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. PKC mediates the induction of NADPH oxidase by transforming growth factor- in endothelial cells.3 Interestingly, PKC seems to mediate inhibitory effects on the superoxide generation by endothelial NADPH oxidase, which is an essential element for the development of endothelial dysfunction.4
In cardiac fibrosis and heart failure, the role of PKC , β, , , and has been investigated intensively. PKC promotes growth factor effects on matrix remodelling,5 increases CTGF and collagen deposition, and mediates hypertrophic signalling, whereas PKC partially opposes these effects.6 Cardiac fibroblast proliferation is induced via PKC activation by transforming growth factor-β and is negatively regulated by PKC.7 This essential mechanism, the inhibitory control on the proliferation of fibroblasts by PKC, seems to be a key mechanism in the development of pulmonary hypertension and pulmonary remodelling in patients with acute respiratory distress syndrome.
In the present issue of Cardiovascular Research, Das et al.8 present findings that demonstrate that hypoxia changes the role of PKC from a negative regulator (replicant repressor) in adventitial pulmonary fibroblast to a stimulator of fibroblast proliferation (replication). The authors explain this phenomenon with the hypothesis that chronic hypoxia leads to a switch of phenotype of adventitial fibroblasts to a proliferative phenotype that lacks the replicant repressor effect of PKC.
Such a phenomenon is clearly not new, but it is a relevant phenomenon in cardiovascular and pulmonary diseases. In the vascular wall, the classical contractile phenotype of VSMCs switches to the secretory type and changes its cellular program to a proinflammatory character, leading to vascular inflammation and formation of vulnerable plaques. Therefore, it appears very likely that the proliferative adventitial fibroblast is a result of a disease-related (hypoxia) phenotype switch. The authors provide further insights in their study which characterize this phenomenon. They demonstrate different phosphorylation profiles of PKC in chronic hypoxic fibroblast populations compared with normal fibroblasts. They demonstrate intranuclear localization of extracellular signal-regulated kinase (ERK) and PKC in hypoxic fibroblasts as molecular events leading to proliferation. Godeny and Sayeski9 have demonstrated that angiotensin II promotes proliferation in VSMCs by a similar mechanism. A heterotrimeric G-protein/PKC complex mediates the translocation of ERK1/2 into the nucleus after stimulation with angiotensin II. Das et al.8 describe a similar mechanism in the chronic hypoxic fibroblast population. It would be interesting to know whether there is an autocrine activator of this mechanism in the hypoxic proliferative population of fibroblasts. Activation by another PKC isoform could also play a role in this concept. Recently, it has been shown that the novel PKC functionally interacts with PKC and PKC, which serve as direct downstream targets in the signalling pathway leading to activation of T-lymphocytes.10
From a clinical viewpoint, pulmonary hyperplasia is a serious and deleterious pathophysiological event in neonatal and critical care medicine that leads to severe pulmonary hypertension and acute respiratory distress syndrome. Here Das et al.8 present new and exciting data that suggest a disease-related phenotype switch of pulmonary fibroblasts under the control of PKC leading to the detrimental hyperplasia in the pulmonary vasculature. These data present pulmonary PKC as a potential target for new therapeutic interventional strategies to prevent pulmonary hypertension, a road which has to be taken.
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The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
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- Das M, Burns N, Wilson SJ, Zawada WM, Stenmark KR. Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKC in the pulmonary artery adventitia. Cardiovasc Res (2008) 78:440–448.
[Abstract/Free Full Text] - Godeny MD, Sayeski PP. ANG II-induced cell proliferation is dually mediated by c-Src/Yes/Fyn-regulated ERK1/2 activation in the cytoplasm and PKCzeta-controlled ERK1/2 activity within the nucleus. Am J Physiol Cell Physiol (2006) 291:C1297–C1307.
[Abstract/Free Full Text] - Gruber T, Fresser F, Jenny M, Uberall F, Leitges M, Baier G. PKCtheta cooperates with atypical PKCzeta and PKCiota in NF-kappaB transactivation of T lymphocytes. Mol Immunol (2008) 45:117–126.[CrossRef][Web of Science][Medline]
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