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Matrix Metalloproteinase‐13 Inhibition is Protective in a Pressure Overload Model of Heart Failure
Author(s) -
Schafer Allison,
ValienteAlandi Iñigo,
Blaxall Burns C.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.939.6
Subject(s) - matrix metalloproteinase , pressure overload , heart failure , fibrosis , extracellular matrix , cardiac fibrosis , medicine , downregulation and upregulation , tissue inhibitor of metalloproteinase , context (archaeology) , ventricular remodeling , endocrinology , cardiology , chemistry , microbiology and biotechnology , biology , biochemistry , cardiac hypertrophy , paleontology , gene
Heart failure (HF) is the leading cause of morbidity and mortality in the United States and is characterized by progressive myocardial fibrosis, pathologic remodeling and deteriorating cardiac function. Cardiac fibrosis occurs due to an imbalance in the production and degradation of the extracellular matrix (ECM). Cardiac fibroblasts (CF) are largely responsible for the secretion of ECM proteins as well as cytokines and growth factors in the heart. Upon injury or pathologic stimulation, CF transition to a myofibroblast phenotype, leading to excess production of ECM proteins and pro‐inflammatory cytokines. Elevated expression of matrix metalloproteinases (MMPs), proteolytic enzymes responsible for maintenance and degradation of the ECM, is common in HF. Specifically, MMP‐13, a collagenase that is not highly expressed in basal conditions, is known to be upregulated in both ischemic and non‐ischemic human HF patients. Previous studies in our lab have also found that chronic β‐adrenergic stimulation, a hallmark of HF, leads to elevated expression and activity of MMP‐13. CF are the major source of MMPs in the heart, thus it is crucial to study MMP‐13 in the context of CF. Therefore, we hypothesize that MMP‐13 plays an important role in pathologic cardiac remodeling, and that inhibition of MMP‐13 will prevent the development of HF in a pressure overload model of HF, transverse aortic constriction (TAC). Mice were subjected to TAC and treated with the MMP‐13 inhibitor, WAY170523 (WAY), or vehicle 4 weeks post‐TAC until 12 weeks post‐TAC. Mice treated with WAY display decreased cardiac hypertrophy and preserved cardiac function compared to vehicle treated mice. Treatment with WAY also appears to attenuate interstitial and perivascular fibrosis as well as expression of pro‐fibrotic genes, Col1a1, Col3a1 and TGF‐β. In order to determine the direct role of MMP‐13 in CF, cells were stimulated with recombinant MMP‐13 or WAY for 24 hours. MMP‐13 stimulation leads to increased pro‐fibrotic and pro‐inflammatory gene expression, as measured by qRT‐PCR. When MMP‐13 is inhibited, CF are less invasive than untreated CF. Inhibition of MMP‐13 does not appear to change CF migration or proliferation. Importantly, MMP‐13 stimulation and WAY treatment do not affect isolated cardiomyocyte contractility. Overall, these data suggest a role for MMP‐13 in pressure overload‐induced HF. Under basal conditions, inhibition of MMP‐13 appears to decrease CF invasion, but does not affect migration or proliferation or cardiomyocyte contractility. However, stimulation of CF with recombinant MMP‐13 leads to increased pro‐fibrotic and pro‐inflammatory gene expression, indicating a possible role for MMP‐13 in the CF to myofibroblast phenotype. Inhibition of MMP‐13 after injury may attenuate this transition, leading to decreased cardiac fibrosis and improved cardiac function. Further understanding of the role of MMP‐13 in the CF could lead to a novel therapeutic target in the treatment of HF. Support or Funding Information This work is supported by 1T32HL125204‐01 (JM, EKG).