2. Academic Validation
  3. FSH Is Responsible for Androgen Deprivation Therapy-Associated Atherosclerosis in Mice by Exaggerating Endothelial Inflammation and Monocyte Adhesion

FSH Is Responsible for Androgen Deprivation Therapy-Associated Atherosclerosis in Mice by Exaggerating Endothelial Inflammation and Monocyte Adhesion

  • Arterioscler Thromb Vasc Biol. 2024 Jan 11. doi: 10.1161/ATVBAHA.123.319426.
Qiang Wang # 1 2,  Jingli Han # 1,  Zhenhui Liang # 3 4,  Xueyu Geng 3 4,  Yiqing Du 1,  Jing Zhou 3 4,  Weijuan Yao 3 4 5,  Tao Xu 1
Affiliations

Affiliations

  • 1 Department of Urology, Peking University People's Hospital, Beijing, China (Q.W., J.H., Y.D., T.X.).
  • 2 Department of Urology, Sichuan Cancer Hospital, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu (Q.W.).
  • 3 Department of Physiology and Pathophysiology, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, China (Z.L., X.G., J.Z., W.Y.).
  • 4 Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China (Z.L., X.G., J.Z., W.Y.).
  • 5 Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University Health Center, Beijing, China (W.Y.).
  • # Contributed equally.
PMID: 38205641 DOI: 10.1161/ATVBAHA.123.319426
Abstract

Background: Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate Cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases.

Methods: We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE-/- mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH Receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms.

Results: Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist-treated mice, blocking of short FSH surge by anti-FSHβ antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist-treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA/CREB/c-Jun and PI3K/Akt/GSK-3β (glycogen synthase kinase 3 beta)/GATA-6 pathways. In monocytes, FSH upregulated CD29 expression via the PI3K/Akt/GSK-3β/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist-induced endothelial inflammation and atherosclerosis in mice.

Conclusions: FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.

Keywords

atherosclerosis; carotid arteries; follicle-stimulating hormone; monocytes; prostatic neoplasms.

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