PMID- 38247525
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240128
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 13
IP  - 1
DP  - 2024 Jan 14
TI  - C2CD4B Evokes Oxidative Stress and Vascular Dysfunction via a 
      PI3K/Akt/PKCalpha-Signaling Pathway.
LID - 10.3390/antiox13010101 [doi]
LID - 101
AB  - 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 PKCalpha 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/PKCalpha-signaling pathway, providing a new perspective on C2CD4B as a 
      promising therapeutic target for the prevention of oxidative stress in 
      diabetes-induced endothelial dysfunction.
FAU - Di Pietro, Paola
AU  - Di Pietro P
AUID- ORCID: 0000-0003-1327-1961
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
FAU - Abate, Angela Carmelita
AU  - Abate AC
AUID- ORCID: 0009-0007-2811-8018
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
FAU - Prete, Valeria
AU  - Prete V
AUID- ORCID: 0009-0006-2380-1611
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
FAU - Damato, Antonio
AU  - Damato A
AD  - Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy.
FAU - Venturini, Eleonora
AU  - Venturini E
AD  - Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy.
FAU - Rusciano, Maria Rosaria
AU  - Rusciano MR
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
FAU - Izzo, Carmine
AU  - Izzo C
AUID- ORCID: 0000-0001-8499-5428
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
FAU - Visco, Valeria
AU  - Visco V
AUID- ORCID: 0000-0002-2197-5355
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
FAU - Ciccarelli, Michele
AU  - Ciccarelli M
AUID- ORCID: 0000-0003-2379-1960
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
FAU - Vecchione, Carmine
AU  - Vecchione C
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
AD  - Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy.
FAU - Carrizzo, Albino
AU  - Carrizzo A
AUID- ORCID: 0000-0003-2689-0008
AD  - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", 
      University of Salerno, 84081 Baronissi, Italy.
AD  - Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy.
LA  - eng
GR  - 2020YRETTX/Research Projects of National Interest (PRIN2020)/
PT  - Journal Article
DEP - 20240114
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC10812653
OTO - NOTNLM
OT  - C2CD4B
OT  - diabetes
OT  - eNOS uncoupling
OT  - endothelial dysfunction
OT  - oxidative stress
COIS- The authors declare no conflicts of interest.
EDAT- 2024/01/22 06:42
MHDA- 2024/01/22 06:43
PMCR- 2024/01/14
CRDT- 2024/01/22 04:23
PHST- 2023/11/29 00:00 [received]
PHST- 2024/01/11 00:00 [revised]
PHST- 2024/01/12 00:00 [accepted]
PHST- 2024/01/22 06:43 [medline]
PHST- 2024/01/22 06:42 [pubmed]
PHST- 2024/01/22 04:23 [entrez]
PHST- 2024/01/14 00:00 [pmc-release]
AID - antiox13010101 [pii]
AID - antioxidants-13-00101 [pii]
AID - 10.3390/antiox13010101 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2024 Jan 14;13(1):101. doi: 10.3390/antiox13010101.