Citronellal can alleviate vascular endothelial dysfunction by reducing ectopic miR-133a expression.

AIMS: Endothelial dysfunction (ED) is the initial cause of atherosclerosis (AS) and an early marker of many cardiovascular diseases (CVD). Citronellal (CT), a monoterpenoid natural product extracted from grass plant Citronella, has been shown to have anti-thrombotic, anti-hypertensive and anti-diabetic cardiomyopathy activities. The aim of this study is to investigate the effects of citronellal on vascular endothelial dysfunction and the underlying mechanisms. MATERIALS AND METHODS: The left common carotid artery was subjected to one-time balloon injury to cause vascular endothelial injury, and the AS model was established by feeding with high-fat diet. Use of HUVECs H2O2 treatment induced HUVECs oxidative stress damage model. The blood lipid level, histopathology, Western blot, immunohistochemistry, RT-PCR, ELISA and in situ fluorescence hybridization of common carotid artery tissues and HUVECs were studied. KEY FINDINGS: CT significantly reduced vascular plate area and endothelial lipid and cholesterol deposition in the common carotid artery of mice in a dose-dependent manner. CT increased the expression of activated protein 2α (AP-2α/TFAP2A) and circRNA_102979, and inhibited the ectopic expression level of miR-133a. However, the constructed lentivirus with AP-2α silencing and circRNA_102979 silencing reversed this phenomenon. SIGNIFICANCE: The current study verifies CT can increase the expression levels of AP-2α and circRNA_102979 in vascular endothelium, increase the adsorption effect of circRNA_102979 on miR-133a and relieve the inhibitory effect of miR-133a on target genes, thereby alleviating AS-induced ED.

Citronellal Attenuates Oxidative Stress-Induced Mitochondrial Damage through TRPM2/NHE1 Pathway and Effectively Inhibits Endothelial Dysfunction in Type 2 Diabetes Mellitus.

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.