Restoration of Mitochondrial Function Is Essential in the Endothelium-Dependent Vasodilation Induced by Acacetin in Hypertensive Rats

Abstract

Mitochondrial dysfunction in the endothelium contributes to the progression of hypertension and plays an obligatory role in modulating vascular tone. Acacetin is a natural flavonoid compound that has been shown to possess multiple beneficial effects, including vasodilatation. However, whether acacetin could improve endothelial function in hypertension by protecting against mitochondria-dependent apoptosis remains to be determined. The mean arterial pressure (MAP) in Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) administered with acacetin intraperitoneally for 2 h or intragastrically for six weeks were examined. The endothelial injury was evaluated by immunofluorescent staining and a transmission electron microscope (TEM). Vascular tension measurement was performed to assess the protective effect of acacetin on mesenteric arteries. Endothelial injury in the pathogenesis of SHR was modeled in HUVECs treated with Angiotensin II (Ang II). Mitochondria-dependent apoptosis, the opening of Mitochondrial Permeability Transition Pore (mPTP) and mitochondrial dynamics proteins were determined by fluorescence activated cell sorting (FACS), immunofluorescence staining and western blot. Acacetin administered intraperitoneally greatly reduced MAP in SHR by mediating a more pronounced endothelium-dependent dilatation in mesenteric arteries, and the vascular dilatation was reduced remarkably by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis. While acacetin administered intragastrically for six weeks had no apparent effect on MAP, it improved the endothelium-dependent dilatation in SHR by activating the AKT/eNOS pathway and protecting against the abnormalities of endothelium and mitochondria. Furthermore, acacetin remarkably inhibited Ang II induced apoptosis by inhibiting the increased expression of Cyclophilin D (CypD), promoted the opening of mPTP, ROS generation, ATP loss and disturbance of dynamin-related protein 1 (DRP1)/optic atrophy1 (OPA1) dynamics in HUVECs. This study suggests that acacetin protected against endothelial dysfunction in hypertension by activating the AKT/eNOS pathway and modulating mitochondrial function by targeting mPTP and DRP1/OPA1-dependent dynamics.

The Antioxidative Effects of Flavones in Hypertensive Disease

“…Xanthohumol, another flavone, has been reported to upregulate mitofusin 2, a mitochondrial profusion factor, to alleviate murine neuronal death in nervous system diseases [39]. Similarly, while hypertension can be spawned by reduced mitochondria fusion, flavonoids have been shown to reverse Angiotensin II-dependent increases in dynamin-related protein 1 (profission) and decreases in optic atrophy 1 (profusion) [40]. These mitochondrial structural changes may have functional impacts on flavone-mediated hypertension.…”

Natural compounds targeting mitochondrial dysfunction: emerging therapeutics for target organ damage in hypertension

“…Research has demonstrated that hypertension induces mitochondrial dysfunction in vascular endothelial and smooth muscle cells, elevating reactive oxygen species generation (Dikalova et al, 2010). Dynamics-related protein 1 (DRP1) activation and optic atrophy protein 1 (OPA1) downregulation impairs mitochondrial dynamics in the small mesenteric arteries of SHRs, leading to an increase in mtROS emission, inflammation, and growth factor signaling, which causes medial thickening and luminal constriction (Li et al, 2022a). Vascular mitochondrial dysfunction can stimulate proliferation and phenotypic switching from contractile to proliferative in vascular smooth muscle cells (VSMCs), resulting in vascular remodeling and stiffness (Lu et al, 2021;Ye et al, 2021).…”

“…Icariin (ICA) is a flavonol glycoside derived from the Chinese medicinal herb Epimedium. It has been used to treat hypertension, Alzheimer's disease, cerebral ischemia, and depression (Li et al, 2022a). Qian et al observed that ICA had a protective effect on cardiac remodeling in SHRs and that oral administration of ICA (20 and 40 mg/kg/day) prevented apoptosis of cardiomyocytes and improved left ventricular remodeling and mitochondrial abnormalities.…”