Genetic and Pharmacological Inhibition of Galectin-3 Prevents Cardiac Remodeling by Interfering With Myocardial Fibrogenesis

Abstract

Background-Galectin-3 has been implicated in the development of organ fibrosis. It is unknown whether it is a relevant therapeutic target in cardiac remodeling and heart failure. Methods and Results-Galectin-3 knock-out and wild-type mice were subjected to angiotensin II infusion (2.5 µg/kg for 14 days) or transverse aortic constriction for 28 days to provoke cardiac remodeling. The efficacy of the galectin-3 inhibitor N-acetyllactosamine was evaluated in TGR(mREN2)27 (REN2) rats and in wild-type mice with the aim of reversing established cardiac remodeling after transverse aortic constriction. In wild-type mice, angiotensin II and transverse aortic constriction perturbations caused left-ventricular (LV) hypertrophy, decreased fractional shortening, and increased LV end-diastolic pressure and fibrosis (P<0.05 versus control wild type). Galectin-3 knock-out mice also developed LV hypertrophy but without LV dysfunction and fibrosis (P=NS). In REN2 rats, pharmacological inhibition of galectin-3 attenuated LV dysfunction and fibrosis. To elucidate the beneficial effects of galectin-3 inhibition on myocardial fibrogenesis, cultured fibroblasts were treated with galectin-3 in the absence or presence of galectin-3 inhibitor. Inhibition of galectin-3 was associated with a downregulation in collagen production (collagen I and III), collagen processing, cleavage, cross-linking, and deposition. Similar results were observed in REN2 rats. Inhibition of galectin-3 also attenuated the progression of cardiac remodeling in a long-term transverse aortic constriction mouse model. Conclusions-Genetic disruption and pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development. Drugs binding to galectin-3 may be potential therapeutic candidates for the prevention or reversal of heart failure with extensive fibrosis. (Circ Heart Fail. 2013;6:107-117.)

Galectin-3 is a marker of myocardial and vascular fibrosis in Kawasaki disease patients with giant aneurysms

“…In the hypertrophied rat heart, activated myocardial macrophages expressed Gal-3, a potent mitogen for fibroblasts, and Gal-3 binding sites were detected on fibroblasts and extracellular matrix [13], suggesting that Gal-3 plays an important role in tissue fibrogenesis. Gal-3 also stimulates differentiation of cardiac fibroblasts into myofibroblasts with attendant increase in collagen production [24]. In this study, we showed that plasma Gal-3 levels were elevated in most of pediatric KD subjects for more than a year.…”

Galectin-3 in acute coronary syndrome

“…Given the observations that Gal-3 has a pivotal role in pathophysiology of adverse cardiac remodeling and it is an independent predictor of HF after ACS, it is reasonable to hypothesize that therapies inhibiting Gal-3 might influence HF progression in high-risk ACS patients [53,54] (Fig. 1).…”

“…MCP, an oligosaccharide present in the peels of fruits and vegetables belonging to Pectin family, inhibits Gal-3 by binding to its CRD domain. In experimental models, MCP was shown to reduce collagen I synthesis and N-Lac to downregulate collagen production, processing, cleavage, cross-linking and deposition [53,61]. Despite preclinical investigations seems to encourage the use of Gal-3 inhibitors to prevent or reduce maladaptive remodeling and, consequently, HF in patients following MI, additional experimental studies and clinical trials are undoubtedly warranted.…”

Effects of anesthesia on conventional and speckle tracking echocardiographic parameters in a mouse model of pressure overload

“…Advancements in transgenic technology have resulted in genetically-modified mice being widely employed as model organisms in mechanistic studies of cardiovascular disease (1,2). The development of accurate and non-invasive techniques for the quantitative and phenotypic characterization of cardiac function in healthy myocardium is crucial for obtaining the full benefits of these models.…”