Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by

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Lele Cheng1,2,3, Liang Wang4, Manyun Guo1,2

  • 1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Clinical Science (London, England : 1979)
|July 9, 2020
PubMed

Insights

Clinically high levels of human C-reactive protein (hCRP) drive hypertension and endothelial dysfunction by inhibiting the AMPK-eNOS pathway. Metformin may offer a therapeutic strategy for patients with elevated hCRP.

Area of Science:

  • Cardiovascular Biology
  • Inflammation Research
  • Hypertension Pathophysiology

Background:

  • Resistant hypertension with elevated human C-reactive protein (hCRP) presents a significant cardiovascular disease challenge.
  • The precise role of high hCRP levels in hypertension pathogenesis is not fully understood, distinguishing between a marker and a causal factor.

Purpose of the Study:

  • To investigate the causal role and underlying mechanisms of clinically relevant high-level hCRP in the development of hypertension.
  • To explore potential therapeutic interventions targeting the identified molecular pathways.

Main Methods:

  • Development and analysis of three distinct hCRP overexpression models (AAV9-transfected mice and rats, hCRP transgenic rats).
  • Assessment of cardiovascular parameters including blood pressure, cardiac hypertrophy, myocardial fibrosis, and endothelial function.
  • Mechanistic studies using endothelial nitric oxide synthase (eNOS) knockout mice and phosphoproteomics to elucidate hCRP's effect on the AMPK-eNOS signaling pathway.
  • Evaluation of metformin's efficacy in modulating endothelial function and blood pressure in hCRP transgenic rats.

Main Results:

  • All hCRP overexpression models exhibited elevated blood pressure.
  • hCRP transgenic rats developed spontaneous hypertension, cardiac hypertrophy, myocardial fibrosis, and impaired endothelium-dependent relaxation.
  • hCRP was found to inhibit the AMP-activated protein kinase (AMPK)-eNOS phosphorylation pathway in endothelial cells.
  • Metformin treatment normalized endothelial-dependent vasodilation and reduced blood pressure in hCRP transgenic rats.

Conclusions:

  • Clinically relevant high-level hCRP acts as a direct driver of hypertension and endothelial dysfunction by disrupting the AMPK-eNOS signaling cascade.
  • hCRP is identified as more than an inflammatory biomarker, playing a causal role in hypertension.
  • Targeting the AMPK pathway with agents like metformin presents a promising therapeutic avenue for hypertension associated with high hCRP levels.

Keywords:
endothelial dysfunctionhuman C-reactive proteinhypertension

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