Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Abstract

Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective Tissue Growth Factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic function in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling were elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted.

Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice

“…Masson trichrome staining showed evidence of interstitial myocardial fibrosis in TmcsMed1 -/- heart (Fig 6A and 6B). Previous studies have shown that interstitial myocardial fibrosis is associated with increased expression of TGFβ2, CTGF and collagenase 9a2 [52,53]. In agreement with this, the TmcsMed1 -/- heart showed elevated expression of the above three genes (Fig 6C, 6D and 6E).…”

Adipose Tissue CTGF Expression is Associated with Adiposity and Insulin Resistance in Humans

“…Data from previous studies have found tissue CTGF expression is upregulated in people with fibrotic diseases, including cirrhosis , cardiac fibrosis , crescentic glomerulonephritis , idiopathic pulmonary fibrosis , and systemic sclerosis . In addition, pharmacological blockade or genetic deletion of CTGF ameliorates the progression of fibrosis in various mouse organs . Together, these findings support the concept that adipose tissue fibrosis is involved in the pathogenesis of insulin resistance associated with obesity in humans, which has previously been demonstrated in rodent models .…”

Expression and clinical significance of connective tissue growth factor (CTGF) in Graves' ophthalmopathy

“…Recently, the profibrogenic cytokine connective tissue growth factor (CTGF, CCN2), a cysteine-rich matricellular protein of the CCN family, has been implicated in mediating a variety of cellular processes, including adhesion, proliferation, differentiation, migration, angiogenesis and extracellular matrix (ECM) production, all of which are common features of tissue remodelling and fibrosis 10 11. Evidence has been introduced and suggested that overexpression of CTGF has been noted in numerous fibrotic disorders, including pulmonary,12 renal,13 hepatic,14 skin15 and cardiac fibrosis 11 16.…”