Citronellal Attenuates Oxidative Stress–Induced Mitochondrial Damage through TRPM2/NHE1 Pathway and Effectively Inhibits Endothelial Dysfunction in Type 2 Diabetes Mellitus
Ya-Ling Yin,
Huan-Huan Wang,
Zi-Chen Gui,
Shan Mi,
Shuang Guo,
Yue Wang,
Qian-Qian Wang,
Rui-Zhu Yue,
Lai-Biao Lin,
Jia-Xin Fan,
Xue Zhang,
Bing-Yan Mao,
Tian-Heng Liu,
Guang-Rui Wan,
He-Qin Zhan,
Mo-Li Zhu,
Lin-Hua Jiang,
Peng Li
Affiliations
Ya-Ling Yin
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
Huan-Huan Wang
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
Zi-Chen Gui
Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Shan Mi
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
Shuang Guo
Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437100, China
Yue Wang
Sanquan College, Xinxiang Medical University, Xinxiang 453003, China
Qian-Qian Wang
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
Rui-Zhu Yue
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
Lai-Biao Lin
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
Jia-Xin Fan
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
Xue Zhang
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
Bing-Yan Mao
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
Tian-Heng Liu
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
Guang-Rui Wan
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
He-Qin Zhan
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
Mo-Li Zhu
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
Lin-Hua Jiang
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
Peng Li
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
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 Ca2+-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.
