ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2015
Hyperglycemia stimulates p62/PKCζ interaction, which mediates NF-κB activation, increased Nox4 expression, and inflammatory cytokine activation in vascular smooth muscle.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 37 citations in OpenAlex.
- Protein Kinase C Family: Structures, Biological Functions, Diseases, and Pharmaceutical Interventions.MedComm · 2025Review
- Novel and Highly Potent Therapeutic Agent, Trametes Robiniophila Murr (Huaier), Mitigates Pulmonary Vascular Remodeling in Rodents.Journal of the American Heart Association · 2025Article
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- Cathelicidin Modulates Vascular Smooth Muscle Cell Phenotypic Switching through ROS/IL-6 Pathway.Antioxidants (Basel, Switzerland) · 2020Article
- Inhibition of protein kinase C beta phosphorylation activates nuclear factor-kappa B and improves postischemic recovery in type 1 diabetes.Experimental biology and medicine (Maywood, N.J.) · 2020Article
- Overexpression of steroid receptor coactivators alleviates hyperglycemia-induced endothelial cell injury in rats through activating the PI3K/Akt pathway.Acta pharmacologica Sinica · 2019Article
- IGF-1 and cardiovascular disease.Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society · 2019Review
- Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1-mediated p53/KLF4 complex stabilization.The Journal of biological chemistry · 2019Article
- Antioxidative Property and Molecular Mechanisms Underlying Geniposide-Mediated Therapeutic Effects in Diabetes Mellitus and Cardiovascular Disease.Oxidative medicine and cellular longevity · 2019Review
- Article
- Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation, proliferation and migration by suppressing ROS/NFκB/mTOR/P70S6K signaling cascade.Redox biology · 2018Article
- Puerarin attenuates diabetic kidney injury through the suppression of NOX4 expression in podocytes.Scientific reports · 2017Article
- Geniposide promotes autophagy to inhibit insulin resistance in HepG2 cells via P62/NF‑κB/GLUT‑4.Molecular medicine reports · 2017Article
- p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1-NF-κB pathway in human ovarian cancer cells.Cancer science · 2017Article
- Protein Scaffolds Control Localized Protein Kinase Cζ Activity.The Journal of biological chemistry · 2016Article
- IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2016Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Hyperglycemia leads to vascular smooth muscle cell (VSMC) dedifferentiation and enhances responses to IGF-I. Prior studies showed that hyperglycemia stimulated NADPH oxidase 4 (Nox4) synthesis, and IGF-I facilitated its recruitment to a signaling complex where it oxidized src, leading to AKT and MAPK activation. To determine the mechanism that led to these changes, we analyzed the roles of p62 (sequestrosome1) and PKCζ. Hyperglycemia induced a 4.9 ± 1.0-fold increase in p62/PKCζ association, and disruption of PKCζ/p62 using a peptide inhibitor or p62 knockdown reduced PKCζ activation (78 ± 6%). 3-Phosphoinoside-dependent protein kinase 1 was also recruited to the p62 complex and directly phosphorylated PKCζ, leading to its activation (3.1 ± 0.4-fold). Subsequently, activated PKCζ phosphorylated p65 rel, which led to increased Nox4 synthesis. Studies in diabetic mice confirmed these findings (6.0 ± 0.4-fold increase in p62/PKCζ) and their disruption of attenuated Nox4 synthesis (76 ± 9% reduction). PKCζ/p62 activation stimulated inflammatory cytokine production and enhanced IGF-I-stimulated VSMC proliferation. These results define the molecular mechanism by which PKCζ is activated in response to hyperglycemia and suggest that this could be a mechanism by which other stimuli such as cytokines or metabolic stress function to stimulate NF-κB activation, thereby altering VSMC sensitivity to IGF-I.
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