Protein kinase C isoforms in atherosclerosis: Pro- or anti-inflammatory?

Fan, Hueng-Chuen; Fernández‐Hernando, Carlos; Lai, Jenn‐Haung

doi:10.1016/j.bcp.2014.01.006

Cited by 38 publications

(32 citation statements)

References 101 publications

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“…Surgical removal of the tumors led to reduction of IL-6 levels as well as regression of key immunologic features in these patients [27]. Given that inflammation plays a critical role in the development of atherosclerosis and cardiovascular disorders [28], it was reported that a long-term increase in IL-6 levels highly correlated with progressively increasing risk of coronary heart disease [29]. Compared to control mice, mice deficient in IL-6 had a significantly lower prevalence as well as severity of autoimmune myocarditis induced by immunization with a cardiac α-myosin peptide [30].…”

Section: Il-6 and Immune-mediated Cardiac Diseasesmentioning

confidence: 99%

“…A c c e p t e d M a n u s c r i p t 28 Anti-IL-6 mAb was generated by immunization of rats with a subcutaneous injection of recombinant human IL-6, and B cells producing specific neutralizing anti-IL-6 antibodies were isolated. After cloning variable region genes from collected B cell and vigorous screening processes, the humanized anti-IL-6 mAb olokizumab that binds human IL-6 with high affinity (KD of 10 pM) was identified [88].…”

Section: Page 28 Of 64mentioning

confidence: 99%

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Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers

Luo

Lai

2015

Biochemical Pharmacology

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Section: Il-6 and Immune-mediated Cardiac Diseasesmentioning

confidence: 99%

Section: Page 28 Of 64mentioning

confidence: 99%

Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers

Luo

Lai

2015

Biochemical Pharmacology

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“…Both PKCβ and δ are potential therapeutic targets as PKCβ potentiates atherosclerotic formation, and PKCδ appears to have an opposite effect (Fan et al, 2014). Depletion of PKCβ gene or treatment with LY333531 in apolipoprotein E-deficient mice decreases atherosclerosis by inhibiting the early growth response (Egr)-1 protein, which regulates VCAM expression and matrix metalloproteinase-2 activity (Harja et al, 2009; Geraldes and King, 2010).…”

Section: Pkc In Vascular Injury and Diseasementioning

confidence: 99%

“…PKC inhibitors could also be useful in treatment of Ca 2+ antagonist-resistant forms of HTN where the Ca 2+ independent PKC isoforms could be targeted (Salamanca and Khalil, 2005). Inhibitors of PKCβ and δ may reduce fat accumulation, improve glucose tolerance, decrease hepatosteatosis, and suppress foam cell formation in obesity and hyperlipidemia-induced atherosclerosis (Bezy et al, 2011; Huang et al, 2012; Fan et al, 2014). Also, a PKCβ inhibitor or PKCɛ activator may reduce damage secondary to endothelial dysfunction and VSMC proliferation in patients with atherosclerosis caused by long-term smoking, HTN or diabetes (Harja et al, 2009; Huang et al, 2010; Monti et al, 2010; Fan et al, 2014).…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders

Ringvold

Khalil

2017

Advances in Pharmacology

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Vascular smooth muscle (VSM) plays an important role in maintaining vascular tone. In addition to Ca2+-dependent myosin light chain (MLC) phosphorylation, protein kinase C (PKC) is a major regulator of VSM function. PKC is a family of conventional Ca2+-dependent α, β, and γ, novel Ca2+-independent δ, ε, θ, and η, and atypical ξ, and ι/λ isoforms. Inactive PKC is mainly cytosolic, and upon activation it undergoes phosphorylation, maturation and translocation to the surface membrane, the nucleus, endoplasmic reticulum, and other cell organelles; a process facilitated by scaffold proteins such as RACKs. Activated PKC phosphorylates different substrates including ion channels, pumps and nuclear proteins. PKC also phosphorylates CPI-17 leading to inhibition of MLC phosphatase, increased MLC phosphorylation and enhanced VSM contraction. PKC could also initiate a cascade of protein kinases leading to phosphorylation of the actin-binding proteins calponin and caldesmon, increased actin-myosin interaction and VSM contraction. Increased PKC activity has been associated with vascular disorders including ischemia-reperfusion injury, coronary artery disease, hypertension, and diabetic vasculopathy. PKC inhibitors could test the role of PKC in different systems, and could reduce PKC hyperactivity in vascular disorders. First generation PKC inhibitors such as staurosporine and chelerythrine are not very specific. Isoform-specific PKC inhibitors such as ruboxistaurin have been tested in clinical trials. Target-delivery of PKC pseudosubstrate inhibitory peptides and PKC siRNA may be useful in localized vascular disease. Further studies of PKC and its role in VSM should help design isoform-specific PKC modulators that are experimentally potent and clinically safe to target PKC in vascular disease.

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“…In T cells, however, a role of PKCβ in T cell locomotion has been demonstrated, where T cells crowling has been shown to be associated with the translocation of PKCβ to the microtubule cytoskeleton [41]. Alterations in PKC expression and/or function may have important implications in health and disease and warrants a detailed investigation into the downstream target genes and the underlying mechanisms involved [42–45]. Further work is needed to identify mechanisms underlying PKCs recruitment or exclusion, potential redundancy, and relevance during immune cells activation.…”

Section: Discussionmentioning

confidence: 99%

Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors

et al. 2015

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Aims of this study were to investigate the ability of RACK1 pseudosubstrate alone or in combination with classical immune stimuli to activate human leukocytes, and to restore age-associated immune defects.A total of 25 donors (17 old donors, 77–79 yrs; 8 young donors, 25–34 yrs) were enrolled. To evaluate the effect of RACK1 pseudosubstrate on cytokine production and CD86 expression the whole blood assay was used. Cultures were treated with RACK1 pseudosubstrate in the presence or absence of lipopolysaccharide (LPS) or phytohaemagglutinin (PHA) and incubated for 24 h or 48 h for LPS-induced CD86 expression, TNF-α, IL-6, IL-8, IL-10 production, and PHA-induced IL-4, IL-10, IFN-γ, respectively. RACK1 pseudosubstrate alone induced IL-6, IL-8, and CD86 expression in both young and old donors, and IFN-γ in old donors. In combination with LPS an increase in IL-8, IL-10 and TNF-α was observed, also resulting in restoration of age-associated defective production, while no changes in the other parameters investigated were found.Even if based on a small sample size, these results suggest the possibility to by-pass some of age-associated immune alterations, which may be beneficial in situations were natural immune stimulation is required, and highlight a different role of PKCβ in immune cells activation.

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Protein kinase C isoforms in atherosclerosis: Pro- or anti-inflammatory?

Cited by 38 publications

References 101 publications

Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers

Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers

Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders

Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors

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