Involvement of angiotensin II type 1 and 2 receptors in gelatinase regulation in human carotid atheroma in vitro

Clancy, Paula, Koblar, Simon, and Golledge, Jonathan (2016) Involvement of angiotensin II type 1 and 2 receptors in gelatinase regulation in human carotid atheroma in vitro. Journal of Atherosclerosis and Thrombosis, 23 (7). pp. 773-719.

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Abstract

Background: Matrix metalloproteinases (MMPs), angiotensin II (AII) and its receptors are implicated in atherosclerotic plaque instability, however the roles of the two receptor subtypes, ATR1 and ATR2, in MMP regulation remain uncertain.

Objective: In this study, we investigated the effect of ATR1 and ATR2 blockade on the expression and activity of MMP-2, MMP-3 and MMP-9, in human carotid atheroma.

Methods: Atheroma samples (n=36) were obtained from patients undergoing carotid endarterectomy. The effects of ATR1 (irbesartan), ATR2 (PD123319) and combined ATR1 and ATR2 blockade on the expression and activity of the MMPs and the expression of tissue inhibitors of metalloproteinases (TIMPs) were investigated in explant culture experiments. Paired atheroma samples were incubated with the intervention or media control for 4 days. Protein levels (MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, TIMP-4, ATR1 and ATR2) were determined by ELISA. Overall gelatinase activity and specific activation were measured by chromogenic activity assays and zymography, respectively.

Results: ATR1 blockade, but not ATR2 blockade significantly reduced TIMP-1, TIMP-2 and TIMP-4 expression in atheroma supernatant. Combined ATR1 and ATR2 blockade significantly reduced MMP-2, MMP-3 and MMP-9 expression. MMP-2 and MMP-9 relative activation, and overall MMP-9 catalytic capacity were significantly increased by ATR1 blockade.

Conclusions: Our findings suggest that ATR1 blockade reduces TIMP expression and increases gelatinase activity in human carotid atheroma.

Item ID: 43716
Item Type: Article (Research - C1)
ISSN: 1880-3873
Keywords: matrix metalloproteinase; gelatinase; tissue inhibitor of matrix; metalloproteinase; angiotensin II receptor; atheroma
Funders: Queensland Tropical Health Alliance (QTHA), Australian Institute of Tropical Health and Medicine (AITHM), National Health and Medical Research Council (NHMRC), Office of Medical Research, Queensland Government
Projects and Grants: NHMRC grant 1011649, NHMRC grant 1003707, NHMRC Practioner Fellowship 1019921
Date Deposited: 16 May 2016 22:34
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 60%
11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 20%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060111 Signal Transduction @ 20%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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