A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women, Menopause, and "Medical Cannabinoids".

Renáta Szabó,Csaba Varga,Krisztina Kupai,Anikó Pósa,Alexandra Hoffmann,Denise Börzsei,István Zupkó,Dániel Priksz,Zsuzsanna Szabó

doi:10.3390/ijms21228801

Renáta Szabó, Csaba Varga + Show 7 more

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https://doi.org/10.3390/ijms21228801

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Abstract

Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E2) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E2 treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions.

Highlights

Epidemiological studies support the strong correlation between endogenous estrogen level and cardiovascular health
Our results clearly showed that the transient potential vanilloid 1 (TRPV1)/calcitonin gene-related peptide (CGRP) system was underactive in estrogen-depleted conditions; these unfavorable changes were reversed as a result of both AEA and estrogen treatment
A large body of evidence exists indicating that the endocannabinoid system plays an important role in the cardiovascular system; its regulatory role is controversial and not fully elucidated

Summary

Introduction

Epidemiological studies support the strong correlation between endogenous estrogen level and cardiovascular health. A growing body of evidence shows that hormone replacement therapy (HRT) decreases the risk of CVDs and reduces mortality in postmenopausal women with heart disease, which is underpinned by the beneficial effects of HRT on vascular tone regulation [4,5]. Human and experimental studies prove that estrogen replacement therapy enhances coronary flow and decreases both coronary resistance and peripheral vascular tone via enhancing nitric oxide (NO) production [6,7]. Many studies reported that the cardiovascular effects of the HO/CO system are similar, at least in part, to those of the NOS/NO system, which indicates a possible relationship between their pathways [9]. Beside estrogen-induced activation of NOS/HO systems, there are myriad pathways and mechanisms that suggest the involvement of enhanced NO/CO release in vascular dilatation and cardiac health

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