Medical College of Wisconsin
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Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 2014 Feb 14;114(4):616-25

Date

12/19/2013

Pubmed ID

24347665

Pubmed Central ID

PMC4186716

DOI

10.1161/CIRCRESAHA.114.302157

Scopus ID

2-s2.0-84894499335   139 Citations

Abstract

RATIONALE: Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.

OBJECTIVE: Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.

METHODS AND RESULTS: Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1α1, 3α1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.

CONCLUSIONS: Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.

Author List

Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG



MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Angiotensin II
Animals
Aortic Diseases
CD4 Antigens
CD8 Antigens
Cells, Cultured
Collagen
Disease Models, Animal
Elastin
Fibroblasts
Homeodomain Proteins
Hypertension
Inflammation
Interleukin-17
Male
Mice
Mice, Knockout
Stress, Mechanical
T-Lymphocytes
Vascular Stiffness
Vasculitis
Vasoconstrictor Agents
p38 Mitogen-Activated Protein Kinases