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Inhibition of CB1R in the Hypothalamic Paraventricular Nucleus Ameliorates Hypertension Through Wnt/β-Catenin/RAS

Hong-Li Gao1, Yu Yang1,2, Hua Tian1,3

  • 1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China.

Cardiovascular Toxicology
|October 29, 2024
PubMed

Insights

Inhibition of the cannabinoid receptor type 1 (CB1R) in the hypothalamic paraventricular nucleus (PVN) reduces hypertension. This occurs via the Wnt/β-catenin/RAS pathway, offering new therapeutic insights.

Area of Science:

  • Neuroscience
  • Cardiovascular Research
  • Pharmacology

Background:

  • The hypothalamic paraventricular nucleus (PVN) is crucial for cardiovascular regulation and hypertension pathogenesis.
  • The endocannabinoid system, particularly the cannabinoid receptor type 1 (CB1R), is implicated in hypertension.
  • The Wnt/β-catenin/RAS pathway is a key signaling system in cardiovascular regulation.

Purpose of the Study:

  • To investigate if inhibiting CB1R in the PVN ameliorates hypertension.
  • To determine the role of the Wnt/β-catenin/RAS pathway in CB1R-mediated hypertension regulation within the PVN.

Main Methods:

  • Spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats received bilateral PVN injections of AM251 (CB1R antagonist) or vehicle for four weeks.
  • Measurements included heart rate, body weight, mean arterial pressure, and protein/gene expression in the PVN.

Main Results:

  • PVN CB1R inhibition with AM251 significantly reduced heart rate, body weight, and mean arterial pressure in SHRs.
  • AM251 altered the expression of CB1R, Wnt3, β-catenin, IKKβ, RAS components, inflammatory cytokines, Glycogen synthase kinase3β, and Superoxide Dismutase in the PVN.
  • These changes indicate modulation of the Wnt/β-catenin/RAS pathway and oxidative stress.

Conclusions:

  • Inhibition of CB1R in the PVN ameliorates hypertension in SHRs.
  • The mechanism involves the modulation of the Wnt/β-catenin/RAS pathway and associated molecular targets.
  • These findings enhance understanding of hypertension's pathological mechanisms and suggest potential therapeutic strategies targeting the PVN CB1R.

Keywords:
Endocannabinoid type 1 receptorHypertensionHypothalamic paraventricular nucleusSympathetic nervous activityWnt/β-catenin/RAS pathway

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