PMID- 36421426
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221126
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 11
IP  - 11
DP  - 2022 Nov 14
TI  - Citronellal Attenuates Oxidative Stress-Induced Mitochondrial Damage through 
      TRPM2/NHE1 Pathway and Effectively Inhibits Endothelial Dysfunction in Type 2 
      Diabetes Mellitus.
LID - 10.3390/antiox11112241 [doi]
LID - 2241
AB  - In type 2 diabetes mellitus (T2DM), oxidative stress induces endothelial 
      dysfunction (ED), which is closely related to the formation of atherosclerosis. 
      However, there are few effective drugs to prevent and cure it. Citronellal (CT) 
      is an aromatic active substance extracted from citronella plants. Recently, CT 
      has been shown to prevent ED, but the underlying mechanism remains unclear. The 
      purpose of this study was to investigate whether CT ameliorated T2DM-induced ED 
      by inhibiting the TRPM2/NHE1 signal pathway. Transient receptor potential channel 
      M2 (TRPM2) is a Ca(2+)-permeable cation channel activated by oxidative stress, 
      which damages endothelial cell barrier function and further leads to ED or 
      atherosclerosis in T2DM. The Na(+)/H(+) exchanger 1 (NHE1), a transmembrane 
      protein, also plays an important role in ED. Whether TRPM2 and NHE1 are involved 
      in the mechanism of CT improving ED in T2DM still needs further study. Through 
      the evaluations of ophthalmoscope, HE and Oil red staining, vascular function, 
      oxidative stress level, and mitochondrial membrane potential evaluation, we 
      observed that CT not only reduced the formation of lipid deposition but also 
      inhibited ED and suppressed oxidative stress-induced mitochondrial damage in 
      vasculature of T2DM rats. The expressions of NHE1 and TRPM2 was up-regulated in 
      the carotid vessels of T2DM rats; NHE1 expression was also upregulated in 
      endothelial cells with overexpression of TRPM2, but CT reversed the up-regulation 
      of NHE1 in vivo and in vitro. In contrast, CT had no inhibitory effect on the 
      expression of NHE1 in TRPM2 knockout mice. Our study show that CT suppressed the 
      expression of NHE1 and TPRM2, alleviated oxidative stress-induced mitochondrial 
      damage, and imposed a protective effect on ED in T2DM rats.
FAU - Yin, Ya-Ling
AU  - Yin YL
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, Department of Physiology and Pathophysiology, School 
      of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China.
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Wang, Huan-Huan
AU  - Wang HH
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Gui, Zi-Chen
AU  - Gui ZC
AD  - Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan 430030, China.
FAU - Mi, Shan
AU  - Mi S
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Guo, Shuang
AU  - Guo S
AD  - Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and 
      Technology, Xianning 437100, China.
FAU - Wang, Yue
AU  - Wang Y
AD  - Sanquan College, Xinxiang Medical University, Xinxiang 453003, China.
FAU - Wang, Qian-Qian
AU  - Wang QQ
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Yue, Rui-Zhu
AU  - Yue RZ
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, Department of Physiology and Pathophysiology, School 
      of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China.
FAU - Lin, Lai-Biao
AU  - Lin LB
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Fan, Jia-Xin
AU  - Fan JX
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Zhang, Xue
AU  - Zhang X
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Mao, Bing-Yan
AU  - Mao BY
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Liu, Tian-Heng
AU  - Liu TH
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Wan, Guang-Rui
AU  - Wan GR
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Zhan, He-Qin
AU  - Zhan HQ
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Zhu, Mo-Li
AU  - Zhu ML
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
FAU - Jiang, Lin-Hua
AU  - Jiang LH
AUID- ORCID: 0000-0001-6398-0411
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, Department of Physiology and Pathophysiology, School 
      of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China.
AD  - School of Biomedical Sciences, Faculty of Biological Sciences, University of 
      Leeds, Leeds LS2 9JT, UK.
FAU - Li, Peng
AU  - Li P
AUID- ORCID: 0000-0003-2030-1807
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, Department of Physiology and Pathophysiology, School 
      of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China.
AD  - Henan International Joint Laboratory of Cardiovascular Remodeling and Drug 
      Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and 
      Molecular Targeted Therapy Drug Development, College of Pharmacy, Xinxiang 
      Medical University, Xinxiang 453003, China.
AD  - Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and 
      Technology, Xianning 437100, China.
LA  - eng
GR  - G2022026006L/National High-End Foreign Expert Recruitment Plan of China/
GR  - 82271460, U1804197, 81874312/National Natural Science Foundation of China/
GR  - 202300410308, HNGD2022067/Research Foundation of Henan Province/
GR  - XYBSKYZZ505319, XYBSKYZZ201626, XYBSKYZZ202202, XYBSKYZZ201907, 2021006ZK, 
      ZD2020006/Research Foundation of Xinxiang Medical University/
PT  - Journal Article
DEP - 20221114
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC9686689
OTO - NOTNLM
OT  - NHE1
OT  - T2DM
OT  - TRPM2
OT  - citronellal
OT  - endothelial dysfunction
COIS- The authors declare no conflict of interest.
EDAT- 2022/11/25 06:00
MHDA- 2022/11/25 06:01
PMCR- 2022/11/14
CRDT- 2022/11/24 09:55
PHST- 2022/11/01 00:00 [received]
PHST- 2022/11/08 00:00 [accepted]
PHST- 2022/11/24 09:55 [entrez]
PHST- 2022/11/25 06:00 [pubmed]
PHST- 2022/11/25 06:01 [medline]
PHST- 2022/11/14 00:00 [pmc-release]
AID - antiox11112241 [pii]
AID - antioxidants-11-02241 [pii]
AID - 10.3390/antiox11112241 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2022 Nov 14;11(11):2241. doi: 10.3390/antiox11112241.