Doxycycline Decreases Atherosclerotic Lesions in the Aorta of ApoE-⁄- and Ovariectomized Mice with Correlation to Reduced MMP-2 Activity

Abstract

Atherogenic events promote changes in vessel walls, with alteration of the redox state, and increased activity of matrix metalloproteinases (MMPs). Thus, this study aims to evaluate aortic remodeling, MMP activity, and reactive oxygen species (ROS) levels after treatment with doxycycline in ApoE-⁄- and ovariectomized mice (OVX). Female ApoE-⁄--knockout mice (5 weeks) were submitted to ovariectomy surgery to induce experimental menopause. They then received chow enriched with 1% cholesterol to induce hypercholesterolemia. The animals were divided into two experimental groups: ApoE-⁄-/OVX vehicle and ApoE-⁄-/OVX doxycycline (30 mg/kg) administered by gavage once a day for 28 days (15th to the 18th week of life). Blood samples were collected to measure total cholesterol and fractions. The aorta was used for morphometry and to measure the activity and expression of MMP-2 and ROS levels. The ApoE-⁄-/OVX doxycycline group showed no change in total and fraction cholesterol levels. However, there was a reduction in ROS levels, MMP-2 expression, and activity that correlated with a decrease in atherosclerotic lesions relative to the ApoE-⁄-/OVX vehicle (p > 0.05). Therefore, we conclude that doxycycline in ApoE-⁄-/OVX animals promotes a reduction in atherosclerotic lesions by reducing ROS and MMP-2 activity and expression.

Female Sex Hormones Contribute to Vulnerability to Athero-Sclerosis: Overview of Mechanisms and Specific Risk Factors

“…However, in a study involving female rabbits on a pro-atherogenic diet, long-term administration of NOS inhibitors caused chronic endothelial dysfunction which aggravated atherosclerosis. The protective effect of E2 was abolished in this setting in intact but not in de-endothelialized vessels (Rodrigues et al, 2022).…”

Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2/GPX4 pathway

“…After menopause, women are more prone to have lipid metabolism disorders and higher levels of aortic ROS, 10,34 resulting in a microenvironment for increased levels of lipid peroxidation in the plaques, which may suggest an increased risk of ferroptosis in vascular resident cells. To test this hypothesis, we detected the levels of lipid peroxidation product 4‐HNE and MDA in the aortic plaque and plasma, respectively.…”

“…13 Recently, the administration of ferroptosis inhibitor Fer-1 alleviated the dyslipidemia and aggravation of atherosclerosis in ApoE −/− mice, which contributed to the further study of the pathogenesis of atherosclerosis. 13 After menopause, women are more prone to have lipid metabolism disorders and higher levels of aortic ROS, 10,34 resulting in a microenvironment for increased levels of lipid peroxidation in the plaques, which may suggest an increased risk of ferroptosis in vascular resident cells. To test this hypothesis, we detected the levels of lipid peroxidation product 4-HNE and MDA in the aortic plaque and plasma, respectively.…”

Molecular Mechanisms Underlying Vascular Remodeling in Hypertension

“…Another mechanism associated with increased oxidative stress is the reduced bioavailability of endothelium-derived vasodilators. In a study conducted by Rodrigues [ 32 ], aortic remodeling, MMP activity, and ROS levels were assessed in apolipoprotein E ( ) and ovariectomized (OVX) mice treated with doxycycline. The findings indicated that the administration of doxycycline resulted in reduced levels of ROS, MMP-2 expression, and activity in /OVX mice, ultimately leading to a decrease in atherosclerotic lesions.…”