RGD Reference Report - Enhanced angiotensin II-mediated effects in fibroblasts of patients with familial hypercholesterolemia. - Rat Genome Database

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Enhanced angiotensin II-mediated effects in fibroblasts of patients with familial hypercholesterolemia.

Authors: Solini, A  Santini, E  Ferrannini, E 
Citation: Solini A, etal., J Hypertens. 2005 Feb;23(2):367-74.
RGD ID: 1582524
Pubmed: PMID:15662225   (View Abstract at PubMed)

OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by a high incidence of coronary heart disease. Evidence suggests an important role for angiotensin II (AngII) in the fibrotic response to tissue injury, and in promoting myocardial hypertrophy via paracrine mechanisms mediated by fibroblasts. We sought to determine whether AngII promotes proliferative and pro-atherogenic responses in FH patients. METHODS: We used primary fibroblasts -- from five patients with heterozygous FH and five control subjects (C) -- to study AngII-induced cell growth, intracellular calcium fluxes, and expression/release of matrix components and pro-inflammatory peptides [transforming growth factor-beta1 (TGFbeta1) and endothelin-1 (ET-1)] and metalloproteinases involved in plaque remodeling and vulnerability. RESULTS: AngII stimulated cell replication (5.1 +/- 0.03 versus 3.2 +/- 0.04 cells/50 cells per well, P < 0.001), and induced a larger increase in intracellular calcium content in FH cells than in C cells, in a dose-dependent fashion (mean difference = 76 nmol/l, P < 0.001). Similarly, TGFbeta1 and ET-1 expression and release were potentiated (after 24-h incubation with 1 micromol/l AngII: TGFbeta1 was 190 +/- 12 in C and 376 +/- 9 pg/ml per 10(6) cells in FH, and ET-1 was 93 +/- 5 in C and 192 +/- 7 pmol/ml per 10(6) cells in FH; P < 0.001 for both). AngII-induced release of the metalloproteinases MMP-1 and MMP-2 was also increased in FH versus C cells (0.52 +/- 0.04 versus 0.36 +/- 0.05 and 24 +/- 4 versus 13 +/- 3 ng/mg protein with 1 micromol/l AngII). These enhanced responses were likely due to an increased angiotensin receptor 1 (AT1) expression in cells from FH patients induced by AngII, and were prevented by pretreating cells with the selective AT1 antagonist irbesartan. CONCLUSIONS: These findings show that some AngII-mediated pathways are enhanced in FH subjects irrespective of the presence of low-density lipoprotein (LDL), thus contributing to the development and progression of atherosclerosis in these patients.

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
atherosclerosis pathway  IDA 1582524 RGD 
atherosclerosis pathway  ISOMMP1 (Homo sapiens)1582524; 1582524 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Mmp1  (matrix metallopeptidase 1)

Genes (Mus musculus)
Mmp1a  (matrix metallopeptidase 1a (interstitial collagenase))

Genes (Homo sapiens)
MMP1  (matrix metallopeptidase 1)


Additional Information