The role of mid-chain hydroxyeicosatetraenoic acids in the pathogenesis of hypertension and cardiac hypertrophy

Arch Toxicol. 2016 Jan;90(1):119-36. doi: 10.1007/s00204-015-1620-8. Epub 2015 Nov 2.


The incidence, prevalence, and hospitalization rates associated with cardiovascular diseases (CVDs) are projected to increase substantially in the world. Understanding of the biological and pathophysiological mechanisms of survival can help the researchers to develop new management modalities. Numerous experimental studies have demonstrated that mid-chain HETEs are strongly involved in the pathogenesis of the CVDs. Mid-chain HETEs are biologically active eicosanoids that result from the metabolism of arachidonic acid (AA) by both lipoxygenase and CYP1B1 (lipoxygenase-like reaction). Therefore, identifying the localizations and expressions of the lipoxygenase and CYP1B1 and their associated AA metabolites in the cardiovascular system is of major importance in understanding their pathological roles. Generally, the expression of these enzymes is shown to be induced during several CVDs, including hypertension and cardiac hypertrophy. The induction of these enzymes is associated with the generation of mid-chain HETEs and subsequently causation of cardiovascular events. Of interest, inhibiting the formation of mid-chain HETEs has been reported to confer a protection against different cardiac hypertrophy and hypertension models such as angiotensin II, Goldblatt, spontaneously hypertensive rat and deoxycorticosterone acetate (DOCA)-salt-induced models. Although the exact mechanisms of mid-chain HETEs-mediated cardiovascular dysfunction are not fully understood, the present review proposes several mechanisms which include activating G-protein-coupled receptor, protein kinase C, mitogen-activated protein kinases, and nuclear factor kappa B. This review provides a clear understanding of the role of mid-chain HETEs in the pathogenesis of cardiovascular diseases and their importance as novel targets in the treatment for hypertension and cardiac hypertrophy.

Keywords: 5, 12, and 15 HETEs; Cytochrome P450; LOX; MAPKs; NF-κB.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cardiomegaly / drug therapy
  • Cardiomegaly / epidemiology
  • Cardiomegaly / metabolism*
  • Cardiomegaly / physiopathology
  • Cardiovascular Agents / therapeutic use
  • Cardiovascular System / drug effects
  • Cardiovascular System / metabolism*
  • Cardiovascular System / physiopathology
  • Cytochrome P-450 CYP1B1 / antagonists & inhibitors
  • Cytochrome P-450 CYP1B1 / metabolism
  • Cytochrome P-450 Enzyme Inhibitors / therapeutic use
  • Drug Design
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Hypertension / drug therapy
  • Hypertension / epidemiology
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Lipoxygenase / metabolism
  • Lipoxygenase Inhibitors / therapeutic use
  • Molecular Targeted Therapy
  • Signal Transduction* / drug effects


  • Cardiovascular Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • Lipoxygenase Inhibitors
  • Lipoxygenase
  • Cytochrome P-450 CYP1B1