NEWS ｜ 12 July 2024

WIKIMOLE—20-HETE

 

By TargetMol

 

20-Hydroxyeicosatetraenoic acid (hereinafter referred to as "20-HETE") is a long-chain fatty acid containing 20 carbon atoms.

20-HETE is a metabolite of arachidonic acid (AA). AA, under the catalysis of the cytochrome P450 (CYP450) enzyme system, particularly the CYP4F2 enzyme, undergoes ω-hydroxylation to introduce a hydroxyl group at the C-20 position, thereby generating 20-HETE. The presence of this hydroxyl group distinguishes 20-HETE from other arachidonic acid metabolites and is crucial for its physiological and pathophysiological functions.

Mechanism of Action

1. Dual Blood Pressure Regulation Effects

20-HETE is a potent vasoconstrictor that can influence the progression of hypertension. In vitro, it promotes the migration and proliferation of vascular smooth muscle cells induced by angiotensin II, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). It acts as a pro-hypertensive agent by constricting peripheral blood vessels and enhancing the vasoconstrictive effects of other vasoactive substances. On the other hand, 20-HETE can inhibit the reabsorption of sodium ions in the proximal tubules and thick ascending limb of the loop of Henle in the kidney, thereby increasing sodium excretion and affecting tubular transport capacity, which acts as an anti-hypertensive effect.

2. Promoting Angiogenesis

Studies have shown that 20-HETE promotes angiogenesis by inducing the proliferation, migration, survival, and tube formation of endothelial cells (EC) and vascular smooth muscle cells (VSMC). It also activates the secretion of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF), from EC and their upstream transcription factor hypoxia-inducible factor 1α (HIF-1α), thereby activating endothelial cells (EC) and vascular smooth muscle cells (VSMC)[3].

 

3. Promoting Tumor Cell Proliferation and Migration

In metastatic breast cancer, 20-HETE can activate multiple intracellular protein kinases, including extracellular signal-regulated kinase (ERK) 1/2, phosphoinositide 3-kinase (PI3K), and protein kinase B (AKT). 20-HETE can also activate growth factors such as vascular endothelial growth factor (VEGF) or receptors such as epidermal growth factor receptor (EGFR), leading to increased proliferation and angiogenesis in U251 glioma cells and MDA-MB-231 metastatic breast cancer cells. Additionally, 20-HETE can stimulate the production of various pro-inflammatory mediators, such as prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α), and chemokines such as interleukin (IL)-8, IL-12, and IL-14.

4. Pro-inflammatory Activity of Endothelial Cells

Vascular inflammation can catalyze the occurrence of various cardiovascular diseases, including atherosclerosis, hypertension, and vascular remodeling. 20-HETE can promote vascular inflammation by activating endothelial cells, leading to increased adhesion molecules and inflammatory cytokines, thereby promoting atherosclerosis and vascular remodeling [2].

Application

1. Drug Development in the Cardiovascular and Cerebrovascular Field

l New Targets for Treating Hypertension

l Angiogenesis

l Cognitive Disorders

 

2. Cancer Target Research

l Metastatic Breast Cancer

l Lung Cancer

l Colorectal Cancer

l Prostate Cancer

References

[1]Chen L, Joseph G, Zhang FF, et al. 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol. 2016;83:57-65.  

[2]Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC. Vascular actions of 20-HETE. Prostaglandins Other Lipid Mediat. 2015;120:9-16.  

[3]Borin TF, Shankar A, Angara K, Rashid MH, Jain M, et al. (2017) HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model. PLOS ONE 12(6): e0178830.

[4]Rocic P, Schwartzman ML. 20-HETE in the regulation of vascular and cardiac function. Pharmacol Ther. 2018;192:74-87.  

[5]Singh H, Cheng J, Deng H, et al. Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension. Hypertension. 2007;50:123–129.

[6]Williams JM, Murphy S, Burke M, Roman RJ. 20-hydroxyeicosatetraeonic acid: a new target for the treatment of hypertension. J Cardiovasc Pharmacol. 2010;56(4):336-344.

[7]Gonzalez-Fernandez E, Liu Y, Auchus AP, Fan F, Roman RJ. Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE. Clin Sci (Lond). 2021;135(15):1929-1944. [10]Borin TF, Angara K, Rashid MH, Achyut BR, Arbab AS. Arachidonic Acid Metabolite as a Novel Therapeutic Target in Breast Cancer Metastasis. Int J Mol Sci. 2017;18(12):2661. Published 2017 Dec 8.  

[8]Jia H, Brixius B, Bocianoski C, Ray S, Koes DR, Brixius-Anderko S. Deciphering the Role of Fatty Acid-Metabolizing CYP4F11 in Lung Cancer and Its Potential As a Drug Target. Drug Metab Dispos. 2024;52(2):69-79. Published 2024 Jan 9.

[9]Chen C, Yang Y, Guo Y, et al. CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer. Cell Death Dis. 2023;14(4):271. Published 2023 Apr 14.  

[10]Cárdenas S, Colombero C, Panelo L, et al. GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865(2):158573.