C2CD4B Evokes Oxidative Stress and Vascular Dysfunction via a PI3K/Akt/PKCα–Signaling Pathway
-
Published:2024-01-14
Issue:1
Volume:13
Page:101
-
ISSN:2076-3921
-
Container-title:Antioxidants
-
language:en
-
Short-container-title:Antioxidants
Author:
Di Pietro Paola1ORCID, Abate Angela Carmelita1ORCID, Prete Valeria1ORCID, Damato Antonio2, Venturini Eleonora2, Rusciano Maria Rosaria1, Izzo Carmine1ORCID, Visco Valeria1ORCID, Ciccarelli Michele1ORCID, Vecchione Carmine12, Carrizzo Albino12ORCID
Affiliation:
1. Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy 2. Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy
Abstract
High glucose–induced endothelial dysfunction is an important pathological feature of diabetic vasculopathy. While genome-wide studies have identified an association between type 2 diabetes mellitus (T2DM) and increased expression of a C2 calcium-dependent domain containing 4B (C2CD4B), no study has yet explored the possible direct effect of C2CD4B on vascular function. Vascular reactivity studies were conducted using a pressure myograph, and nitric oxide and oxidative stress were assessed through difluorofluorescein diacetate and dihydroethidium, respectively. We demonstrate that high glucose upregulated both mRNA and protein expression of C2CD4B in mice mesenteric arteries in a time-dependent manner. Notably, the inhibition of C2CD4B expression by genetic knockdown efficiently prevented hyperglycemia–induced oxidative stress, endothelial dysfunction, and loss of nitric oxide (NO) bioavailability. Recombinant C2CD4B evoked endothelial dysfunction of mice mesenteric arteries, an effect associated with increased reactive oxygen species (ROS) and decreased NO production. In isolated human umbilical vein endothelial cells (HUVECs), C2CD4B increased phosphorylation of endothelial nitric oxide synthase (eNOS) at the inhibitory site Thr495 and reduced eNOS dimerization. Pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and PKCα effectively attenuated oxidative stress, NO reduction, impairment of endothelial function, and eNOS uncoupling induced by C2CD4B. These data demonstrate, for the first time, that C2CD4B exerts a direct effect on vascular endothelium via a phosphoinositide 3-kinase (PI3K)/Akt/PKCα–signaling pathway, providing a new perspective on C2CD4B as a promising therapeutic target for the prevention of oxidative stress in diabetes–induced endothelial dysfunction.
Subject
Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology
Reference57 articles.
1. NCD Risk Factor Collaboration (NCD-RisC) (2016). Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants. Lancet, 387, 1513–1530. 2. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition;Saeedi;Diabetes Res. Clin. Pract.,2019 3. Vascular complications of diabetes: Mechanisms of injury and protective factors;King;Cell Metab.,2013 4. Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus;Schiattarella;J. Am. Heart Assoc.,2018 5. Carrizzo, A., Izzo, C., Oliveti, M., Alfano, A., Virtuoso, N., Capunzo, M., Di Pietro, P., Calabrese, M., De Simone, E., and Sciarretta, S. (2018). The Main Determinants of Diabetes Mellitus Vascular Complications: Endothelial Dysfunction and Platelet Hyperaggregation. Int. J. Mol. Sci., 19.
|
|