Crosstalk between mitochondrial homeostasis and AMPK pathway mediate the receptor-mediated cardioprotective effects of estradiol in ovariectomized female rats

• Published in: PloS one 2024-12, Vol.19 (12), p.e0312397
• Main Authors: Gowayed, Mennatallah A, Zakaraya, Zainab Zaki, Abu-Samra, Nehal, Elhamammy, Reem H, Abdel Moneim, Lobna M, Hafez, Hala A, Moneam, Ihab A, Oriquat, Ghaleb A, Kamel, Maher A
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Adenosine kinase; Adenosine monophosphate; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Analysis; Animals; Autophagy; Autophagy - drug effects; Biology and Life Sciences; Biosynthesis; Cardiotonic Agents - pharmacology; Cardiovascular diseases; Cardiovascular system; Care and treatment; Cholesterol; Crosstalk; Diagnosis; Dyslipidemia; Estradiol - pharmacology; Estrogen; Estrogen receptors; Estrogens; Female; Females; Fulvestrant; Fulvestrant - pharmacology; Genes; Health aspects; Heart diseases; High density lipoprotein; Homeostasis; Homeostasis - drug effects; Kinases; Laboratory animals; Lipids; Medicine and Health Sciences; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Mitochondrial DNA; Mitochondrial Dynamics - drug effects; Mitophagy; Mitophagy - drug effects; Nitric oxide; Ovariectomy; Peptides; Polymerase chain reaction; Post-menopause; Post-translation; Proteins; Rats; Receptors; Receptors, Estrogen - metabolism; Research and Analysis Methods; Risk factors; Sex hormones; Signal transduction; Signal Transduction - drug effects; Subgroups; Variance analysis; Xenoestrogens
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0312397

Estrogen (E2) deficiency is a risk factor for cardiovascular disease (CVD), however, the exact mechanism for the E2 protective effect on CVD remains unclear. This study aimed to investigate the estrogen receptor (ER) and non-receptor mediated effects of E2 treatment on the cardiac expression of adenosine monophosphate-dependent protein kinase (AMPK), autophagic, mitophagy and mitochondrial homeostasis-regulating genes in ovariectomized (OVX) rats. Female rats were divided into two main groups; sham and bilaterally OVX rats, then each group was subdivided into four subgroups according to treatment; untreated, subcutaneously treated with E2 (30 μg/kg), or Fulvestrant (F) (5 mg/Kg), or a combination of both drugs for 28 days. The OVX rats or F-treated sham rats showed dyslipidemia, and marked disturbances in parameters of AMPK signaling, autophagy, mitophagy, mitochondrial fission, fusion and biogenesis. E2 administration to OVX or F-treated sham rats has corrected the disturbed lipid and cardiac profiles, increased AMPK, and restored the balance of cardiac autophagy, mitophagy, and mitochondrial dynamics and homeostasis. Most of these effects in OVX rats were blocked by the ER antagonist (F). Estrogen treatment has cardioprotective effects in OVX females through modulating cardiac mitochondrial homeostasis, mitophagy and autophagy and restoring the AMPK signaling pathway. As witnessed by Fulvestrant, these effects suggest the main role of ER-mediated signaling in regulating mitophagy and plasma and cardiac lipids along with the existence of a post-translational control mechanism or the involvement of estrogenic non-receptor pathway controlling the postmenopausal cardiac mitochondrial energy production machinery that needs further investigation.