Hormone Replacement Therapy and Aging: A Potential Therapeutic Approach for Age-Related Oxidative Stress and Cardiac Remodeling.

Renáta Szabó,Alexandra Hoffmann,Imre Pávó,Csaba Varga,Béla Juhász,Rudolf Gesztelyi,Médea Veszelka,Zsolt Turcsán,Anikó Magyariné Berkó,Krisztina Kupai,Anikó Pósa,Denise Börzsei

doi:10.1155/2021/8364297

Abstract

Advanced age is an independent risk factor for cardiovascular diseases, which might be further exacerbated by estrogen deficiency. Hormone replacement therapy (HRT) decreases cardiovascular risks and events in postmenopausal women; however, its effects are not fully elucidated in older individuals. Thus, the aim of our study is to examine the impact of HRT on oxidant/antioxidant homeostasis and cardiac remodeling. In our experiment, control (fertile) and aging (~20-month-old) female Wistar rats were used. Aging rats were further divided into estrogen- (E2, 0.1 mg/kg/day per os) or raloxifene- (RAL, 1.0 mg/kg/day per os) treated subgroups. After 2 weeks of treatment, cardiac heme oxygenase (HO) activity, total glutathione (GSH) content, matrix metalloproteinase-2 (MMP-2) activity, and the concentrations of collagen type I and tissue inhibitor of metalloproteinase (TIMP-2), as well as the infarct size, were determined. The aging process significantly decreased the antioxidant HO activity and GSH content, altered the MMP-2/TIMP-2 signaling, and resulted in an excessive collagen accumulation, which culminated in cardiovascular injury. However, 2 weeks of either E2 or RAL treatment enhanced the antioxidant defense mechanisms and attenuated cardiac remodeling related to aging. Our findings clearly show that 2-week-long HRT is a potential intervention to bias successful cardiovascular aging via reducing oxidative damage and cardiovascular dysfunction.

Highlights

Cardiac senescence is characterized by morphological and functional changes that render the heart and vasculature to be prone to cardiovascular diseases (CVDs)
Our results show that the aging process resulted in a 70% decrease in the matrix metalloproteinase-2 (MMP-2) activity compared to the control group
The reduction of estrogen synthesis, changes in estrogen receptors, and alterations of signaling pathways related to the aging process increase the risk of complex cardiovascular damages [18]

Summary

Introduction

Cardiac senescence is characterized by morphological and functional changes that render the heart and vasculature to be prone to cardiovascular diseases (CVDs). The mechanisms underlying cardiovascular aging are complex and involve multiple pathways, a growing body of evidence shows that chronic oxidative stress is a key factor in the incidence and progression of CVDs [1,2,3]. High levels of reactive oxygen species (ROS) may play a critical role in the cellular damage during aging and lead to an imbalance between the oxidant and antioxidant systems [4]. Age-related GSH depletion is associated with ROS overproduction and makes the heart more vulnerable to macromolecular damage affecting the physiological mechanisms and function [6]. Due to the impaired endogenous defense systems and increased production of ROS, oxidative stress-induced pathways lead to maladaptive fibrotic processes in the myocardium, promoting the development of pathological cardiac remodeling. Ageassociated cardiomyocyte loss and excessive collagen deposition (i.e., fibrosis) result in the critical deterioration of the extracellular matrix [9]

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