Connective Tissue Growth Factor Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in Pressure Overload–Induced Heart Failure

Abstract

Connective tissue growth factor (CTGF) is involved in the pathogenesis of various fibrotic disorders. However, its role in the heart is not clear. To investigate the role of CTGF in regulating the development of cardiac fibrosis and heart failure, we subjected mice to thoracic aortic constriction (TAC) or angiotensin II infusion, and antagonized the function of CTGF with CTGF monoclonal antibody (mAb). After 8 weeks of TAC, mice treated with CTGF mAb had significantly better preserved left ventricular (LV) systolic function and reduced LV dilatation compared with mice treated with control immunoglobulin G. CTGF mAb–treated mice exhibited significantly smaller cardiomyocyte cross-sectional area and reduced expression of hypertrophic marker genes. CTGF mAb treatment reduced the TAC-induced production of collagen 1 but did not significantly attenuate TAC-induced accumulation of interstitial fibrosis. Analysis of genes regulating extracellular matrix proteolysis showed decreased expression of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 in mice treated with CTGF mAb. In contrast to TAC, antagonizing the function of CTGF had no effect on LV dysfunction or LV hypertrophy in mice subjected to 4-week angiotensin II infusion. Further analysis showed that angiotensin II–induced expression of hypertrophic marker genes or collagens was not affected by treatment with CTGF mAb. In conclusion, CTGF mAb protects from adverse LV remodeling and LV dysfunction in hearts subjected to pressure overload by TAC. Antagonizing the function of CTGF may offer protection from cardiac end-organ damage in patients with hypertension.

Genetic Analysis of Connective Tissue Growth Factor as an Effector of Transforming Growth Factor β Signaling and Cardiac Remodeling

“…These observations are in contrast to a recent report showing that systemic administration of a monoclonal antibody (MAb) against CTGF in mice over 8 weeks of TAC stimulation preserved cardiac function better and reduced left ventricular dilation but without reducing cardiac fibrosis (42).…”

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…Cardiac fibroblasts not only produce extracellular matrix proteins, but also secrete a variety of growth factors that mediate an interplay between cardiac fibroblasts and cardiomyocytes. Several growth factors, such as Ang II, ET‐1, and platelet‐derived growth factor, and various cytokines, such as transforming growth factor‐beta (TGFβ) and connective tissue growth factor (CTGF), have been proposed to act in either para‐ or autocrine fashion between fibroblasts and cardiomyocytes to stimulate cardiac remodeling 37, 38. Multiple studies now indicate that NPs also directly affect the function of cardiac fibroblasts and cardiomyocytes.…”

Clinical efficacy of dual inhibitor of neprilisin and AT1‑angiotensin receptors LCZ696 (sakubitril/valsartan) in chronic heart failure patients with impaired renal function

“…Продуцируемые кардиомиоцитами ПНП и МНП не только поступают в общий кровоток, но аутокринным и паракринным способом влияют на функциональное состояние самих кардиомиоцитов и интерстициальных фибробластов, которые, выделяя профибротические цитокины и факторы роста, участвуют при ХСН в фибро-тическом повреждении, гипертрофии и ремоделировании миокарда желудочков [17,18]. Многочисленные экспери-ментальные данные показывают, что оба НУП, активируя внутриклеточный ГЦР-А / ГЦ / цГМФ-сигнальный путь, препятствуют патологическим эффектам основного про-фибротического цитокина TGF-β 1 (трансформирующего фактора роста β 1 ), индуцирующего в миокарде проли-ферацию интерстициальных фибробластов и избыточ-ную продукцию белков внеклеточного матрикса [19][20][21].…”