Open AccessPressure overload-dependent membrane type 1-matrix metalloproteinase induction: relationship to LV remodeling and fibrosis
Author(s) -
Michael R. Zile,
Catalin F. Baicu,
Robert E. Stroud,
An Van Laer,
Jazmine E. Arroyo,
Rupak Mukherjee,
Jeffrey A. Jones,
Francis G. Spinale
Publication year - 2012
Publication title -
american journal of physiology. heart and circulatory physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.524
H-Index - 197
eISSN - 1522-1539
pISSN - 0363-6135
DOI - 10.1152/ajpheart.00580.2011
Subject(s) - medicine , endocrinology , in vivo , luciferase , matrix metalloproteinase , extracellular matrix , fibrosis , pressure overload , chemistry , biology , biochemistry , muscle hypertrophy , transfection , microbiology and biotechnology , cardiac hypertrophy , gene
Increased myocardial extracellular matrix collagen represents an important structural milestone during the development of left ventricular (LV) pressure overload (PO); however, the proteolytic pathways that contribute to this process are not fully understood. This study tested the hypothesis that membrane type 1-matrix metalloproteinase (MT1-MMP) is directly induced at the transcriptional level in vivo during PO and is related to changes in LV collagen content. PO was induced in vivo by transverse aortic constriction in transgenic mice containing the full length human MT1-MMP promoter region ligated to luciferase (MT1-MMP Prom mice). MT1-MMP promoter activation (luciferase expression), expression, and activity; collagen volume fraction (CVF); and left atrial dimension were measured at 1 (n = 8), 2 (n = 12), and 4 (n = 17) wk following PO. Non-PO mice (n = 10) served as controls. Luciferase expression increased by fivefold at 1 wk, fell at 2 wk, and increased again by ninefold at 4 wk of PO (P < 0.05). MT1-MMP expression and activity increased at 1 wk, fell at 2 wk, and increased again at 4 wk after PO. CVF increased at 1 wk, remained unchanged at 2 wk, and increased by threefold at 4 wk of PO (P < 0.05). There was a strong positive correlation between CVF and MT1-MMP activity (r = 0.80, P < 0.05). Left atrial dimension remained unchanged at 1 and 2 wk but increased by 25% at 4 wk of PO. When a mechanical load was applied in vitro to LV papillary muscles isolated from MT1-MMP Prom mice, increased load caused MT1-MMP promoter activation to increase by twofold and MT1-MMP expression to increase by fivefold (P < 0.05). These findings challenge the canonical belief that PO suppresses overall matrix proteolytic activity, but rather supports the concept that certain proteases, such as MT1-MMP, play a pivotal role in PO-induced matrix remodeling and fibrosis.