(P23-083-23) Ganoderic Acid A Ameliorates Endothelial Dysfunction in Estrogen-deficient Mice

Objectives: Estrogen deficiency is a problem faced by menopausal and postmenopausal women, it increases the risk of cardiovascular diseases (CVDs). CVDs are the leading cause of death all over the world. Most of the risk factors for CVDs have been linked to endothelial dysfunction. This study is aimed to investigate whether Ganoderic Acid A (GA A) prevents endothelial dysfunction in ovariectomized mice and clarify the underlying mechanisms.

Methods: Female mice were randomized into four groups: (1) Sham: mice received sham surgery. (2) OVX: mice were bilateral ovariectomized. (3) OVX+GA A: mice were bilateral ovariectomized and receive GA A treatment by oral gavage. (4) OVX+E₂: mice were bilateral ovariectomized and receive 17β-estradiol treatment by implanting sustained-release tablets subcutaneously. The ovariectomized mice were held for 12 weeks to induce estrogen-deficiency and endothelial dysfunction. Afterwards, the mice in OVX+GA A group were administered GA A (50 mg/kg body weight in 0.3% CMC-Na) via oral gavage while mice in other groups were administered by 0.3% CMC-Na for 8 weeks. At the endpoint of the study, mice aortas were collected for wire myograph study, qPCR analysis and Dihydroethidium staining.

Results: The endothelium-dependent relaxations were reduced by ovariectomy. However, this reduction was ameliorated after oral administration of GA A. Similar endothelium-independent relaxations were observed in each group. Also, The Reactive Oxygen Species (ROS) levels were increased in the aortas from OVX group, while this increase was reversed in the aortas from OVX+GA A group. The qPCR analysis showed that GA A downregulated transcriptional levels of Grp78 and ATF6α, which are related to ER stress. GA A also upregulated mRNA levels of antioxidant genes (CAT, GPx1, UCP-1, SOD-1, SOD-2 and SOD-3) and decreased mRNA levels of apoptosis markers (CASP3, CASP7) and pro-inflammatory genes (ICAM-1, MCP-1 and NLRP3) in aortas of ovariectomized mice.

Conclusions: GA A ameliorates endothelial dysfunction by decreasing ROS levels and inhibiting ER stress pathway involving Grp78 and ATF6α in ovariectomized mice aortas. Studying the protective effect of GA A on the endothelium can provide a new perspective for the treatment of CVDs on estrogen-deficient women.

Funding Sources: State Key Laboratory of Agrobiotechnology (The Chinese University of Hong Kong)