Supraphysiological levels of testosterone induces endothelial injury via increasing generation of reactive oxygen species and ERK1/2 activation

活性氧 超氧化物歧化酶 超氧化物 内科学 内皮功能障碍 内分泌学 脐静脉 内皮干细胞 生物 氧化应激 氮氧化物4 内皮 NADPH氧化酶 炎症 细胞内 分子生物学 细胞生物学 生物化学 医学 体外
作者
Juliano Alves,Rafael M. Costa,Wanessa M.C. Awata,Shubhnita Singh,Ariane Bruder‐Nascimento,Gabriela Rodrigues Barbosa,Thiago Bruder‐Nascimento
出处
期刊:Physiology [American Physiological Society]
卷期号:38 (S1)
标识
DOI:10.1152/physiol.2023.38.s1.5733006
摘要

Introduction: High levels of testosterone (Testo) is associated with higher cardiovascular risk by positively modulate the generation of reactive oxygen species (ROS) and inflammatory response. Excessive ROS generation by NADPH oxidases (NOX, major source of ROS in the vasculature) leads to endothelial dysfunction, apoptosis, and inflammation. However, the intracellular mechanisms whereby supraphysiological levels of Testo promote cardiovascular damage are still ill defined. We sought to determine whether supraphysiological levels of Testo induces endothelial cell dysfunction via ROS generation and ERK1/2 activation. Methods: To study whether Testo present the same effects independent on endothelial cell type, we used Primary Human Mesenteric vascular Endothelial Cells (HMEC) and Human Umbilical Vein Endothelial Cells (HUVEC). Cells were stimulated with Testo (10 −7 M, for different time points) in the presence or absence of superoxide dismutase mimetic (Tempol, 10 -4 M, for 30 min). NOX activity, gene expression, and protein expression were determined pharmacological assays and immunoblotting, respectively. Results: Testo increased superoxide anion (O 2 − ) generation in HMEC and HUVEC at short (10 min) stimulation times, which was abolished by superoxide dismutase (SOD) mimetic [(% of control) Ctrl: 100.0 ± 0.0 n=5 vs Testo: 363.2 ± 19.77 n=6 vs. Tempol+Testo: 156.7 ± 12.12 n=6, *P<0.05]. Furthermore, long-term treatment (24 h) of endothelial cells with Testo increased Nox4 expression at gene (2.44-Fold change) and protein levels [(% of control) Ctrl: 100.0 ± 0.0 n=4 vs. Testo: 157.3 ± 4.49 n=4, *P<0.05]. Testo did not affect Nox1, Nox2, and Nox5 expressions. Furthermore, Testo increased ERK1/2 phosphorylation at 10 minutes and promoted endothelial cell inflammation at 8h, characterized by increased ICAM-1(6.49-Fold changes) and VCAM-1 [(1.42-Fold changes) gene expressions. To confirm that Testo-induced ROS production is leading to endothelial injury via ERK1/2, we treated endothelial cells with Tempol prior Testo treatment. Interestingly, superoxide dismutase mimetic prevented ERK1/2 phosphorylation induced by Testo [(% of control) Testo: 161.2 ± 11.39 n=5 vs. Tempol+Testo: 91.45 ± 9.61 n=5, *P<0.05]. Conclusion: These data indicate that supraphysiological levels of testosterone induce endothelial dysfunction via ROS generation and inflammatory response. Our data helps understanding the intracellular mechanisms that justify the cardiovascular damage caused by supraphysiological doses of testosterone and places antioxidant therapy as a possible pharmacological approach to treat patients with dysregulated testosterone levels. 2022/00103-3, São Paulo Research Foundation (FAPESP). NHLBI-R00 (R00HL14013903), AHA-CDA (CDA857268), Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania Vitalant, and Children's Hospital of Pittsburgh of the UPMC Health System. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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