Liraglutide improves adipose tissue remodeling and mitochondrial dynamics in a visceral obesity model induced by a high-fat diet.

Central obesity is characterized by visceral adipose tissue (VAT) expansion, considered one of the main risk factors for metabolic complications. In recent years, new drugs have been studied for obesity treatment. Liraglutide (LGT), a GLP-1 agonist, decreases body weight, however, several mechanisms of action on VAT are still unknown. Aim: to study the effect of LGT on factors associated with VAT remodeling and mitochondrial dynamics in mice fed a high-fat diet (HFD). Methods: C57BL/6 mice were divided into Control (C) and HFD. After 15 weeks of feeding, each group was subdivided according to LGT administration for 5 weeks: C, C + LGT, HFD, and HFD + LGT. In epididymal AT (EAT) we evaluated histological and mitochondrial characteristics, vascularity, gelatinase activity (MMPs), and galectin-3 expression. Results: HFD presented larger adipocytes (p < 0.05), and lower vascular density and MMP-9 activity (p < 0.01) than C, while a major number of smaller adipocytes (p < 0.05) and an increase in vascularity (p < 0.001) and MMP-9 activity (p < 0.01) was observed in HFD + LGT. Collagen content was higher (p < 0.05) in EAT from HFD and decreased in HFD + LGT. In C, C + LGT, and HFD + LGT, mitochondria were predominantly tubular-shaped while in HFD mitochondria were mostly spherical (p < 0.001). Conclusion: LGT positively influences VAT behavior by modulating gelatinase activity, enhancing vascularization, and improving adipocyte histological characteristics. Additionally, LGT improves mitochondrial dynamics, a process that would favor VAT functionality.

Galectin-3 contributes to acute cardiac dysfunction and toxicity by increasing oxidative stress and fibrosis in doxorubicin-treated mice.

BACKGROUND: Doxorubicin (DOX) leads to cardiovascular toxicity through direct cardiomyocyte injury and inflammation. We aimed to study the role of Galectin-3 (Gal-3), a ß-galactosidase binding lectin associated with inflammation and fibrosis in DOX-induced acute cardiotoxicity in mice. METHODS: Male C57 and Gal-3 knockout (KO) mice were given a single dose of DOX (15 mg/kg, i.p) or placebo. Serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and cardiac thiobarbituric acid-reactive substance (TBARS) were measured at 3 days to assess cardiac injury and oxidative stress. Cardiac remodeling and function were studied by echocardiography and catheterization at 7 days. Myocardial fibrosis was quantified in picrosirius red stained slices. RESULTS: Absence of Gal-3 tended to reduce the mortality after DOX. DOX significantly increased CPK, LDH, AST and TBARS while treated Gal-3 KO mice showed reduced injury and oxidative stress. After 7 days, adverse remodeling, fibrosis and dysfunction in treated-C57 mice were severely affected while those effects were prevented by absence of Gal-3. CONCLUSION: In summary, genetic deletion of Gal-3 prevented cardiac damage, adverse remodeling and dysfunction, associated with reduced cardiac oxidative stress and fibrosis. Understanding the contribution of GAL-3 to doxorubicin-induced cardiac toxicity reinforces its potential use as a therapeutic target in patients with several cancer types.

An Experimental Model of Myocardial Infarction for Studying Cardiac Repair and Remodeling in Knockout Mice.

Cardiovascular disease is the most prevalent cause of death in Western countries, with acute myocardial infarction (MI) being the most prevalent form. This paper describes a protocol for studying the role of galectin 3 (Gal-3) in the temporal evolution of cardiac healing and remodeling in an experimental animal model of MI. The procedures described include an experimental model of MI with a permanent coronary ligature in male C57BL/6J (control) and Gal-3 knockout (KO) mice, an echocardiography procedure to study cardiac remodeling and systolic function in vivo, a histological evaluation of interstitial myocardial fibrosis with picrosirius red-stained and rhodamine-conjugated lectin-stained sections for studying myocyte hypertrophy by the cross-sectional area (MCSA), and the quantification of infarct size and cardiac remodeling (scar thinning, septum thickness, and expansion index) by planimetry in slices stained with Masson's trichrome and triphenyl tetrazolium chloride. Gal-3 KO mice with MI showed disrupted cardiac remodeling and an increase in the scar thinning ratio and the expansion index. At the onset of MI, myocardial function and cardiac remodeling were also severely affected. At 4 weeks post MI, the natural evolution of fibrosis in infarcted Gal-3 KO mice was also affected. In summary, the experimental model of MI is a suitable model for studying the temporal evolution of cardiac repair and remodeling in mice with the genetic deletion of Gal-3 and other animal models. The lack of Gal-3 affects the dynamics of cardiac repair and disrupts the evolution of cardiac remodeling and function after MI.

Genetic Deletion of Galectin-3 Exacerbates Age-Related Myocardial Hypertrophy and Fibrosis in Mice.

BACKGROUND/AIMS: Aging is accompanied by progressive and adverse cardiac remodeling characterized by myocardial hypertrophy, fibrosis, and dysfunction. We previously reported that galectin-3 (Gal-3) is a critical regulator of inflammation and fibrosis associated with hypertensive heart disease and myocardial infarction. Nevertheless, the role and mechanism of Gal-3 in age-related cardiac remodeling have not been previously investigated. We hypothesized that Gal-3 plays a critical role in cardiac aging and that its deficiency exacerbates the underlying mechanisms of myocardial hypertrophy and fibrosis. METHODS: Male C57BL/6 (control) (n=24) and Gal-3 knockout (KO) (n=29) mice were studied at 24 months of age to evaluate the role of Gal-3 in cardiac aging. We assessed 1) survival rate; 2) systolic blood pressure (SBP) by plethysmography; 3) myocardial hypertrophy, apoptosis, and fibrosis by quantification of histological and immunohistochemical analysis; 4) cardiac expression of angiotensin (Ang) II, Ang (1-7) by Radioimmunoassay; 5) transforming growth factor-ß (TGF-ß), sirtuin (SIRT) 1, SIRT 7 and metalloproteinase 9 (MMP-9) by RT-qPCR and 6) ventricular remodeling and function by echocardiography. RESULTS: We found that aged Gal-3 KO mice had a lower survival rate and exhibited exacerbated myocardial hypertrophy and fibrosis without changes in SBP. Similarly, myocardial apoptosis and MMP-9 mRNA expression was significantly increased in the hearts of Gal-3 KO mice compared to controls. Additionally, cardiac Ang II and TGF-ß expression were higher in aged Gal-3 KO mice while SIRT1 and SIRT7 expression were reduced. CONCLUSION: Our findings strongly suggest that Gal-3 is involved in age-related cardiac remodeling by regulating critical mechanisms associated with the development of pathological hypertrophy. The gene deletion of Gal-3 reduced the lifespan and markedly increased age-dependent mechanisms of myocardial hypertrophy, apoptosis, and fibrosis, including Ang-II, TGF-ß, and MMP-9. At the same time, there was diminished cardiac-specific expression of SIRT1 and SIRT7, which are extensively implicated in delaying age-dependent cardiomyopathies.

Genetic Deletion of Galectin-3 Alters the Temporal Evolution of Macrophage Infiltration and Healing Affecting the Cardiac Remodeling and Function after Myocardial Infarction in Mice.

We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2) on macrophage, cytokines, and fibrosis through the temporal evolution of healing, ventricular remodeling, and function after myocardial infarction (MI). C57BL/6J and Gal-3 knockout mice (Lgals3-/-) were subjected to permanent coronary ligation or sham. We studied i) mortality, ii) macrophage infiltration and expression of markers of alternative activation, iii) cytokine, iv) matrix metalloproteinase-2 activity, v) fibrosis, and vi) cardiac function and remodeling. At 1 week post-MI, lack of Gal-3 markedly attenuated F4/80+ macrophage infiltration and significantly increased the expression of Mrc1 and Chil1, markers of M2 macrophages at the MI zone. Levels of IL-10, IL-6, and matrix metalloproteinase-2 were significantly increased, whereas tumor necrosis factor-α, transforming growth factor-ß, and fibrosis were remarkably attenuated at the infarct zone. In Gal-3 knockout mice, scar thinning ratio, expansion, and cardiac remodeling and function were severely affected from the onset of MI. At 4 weeks post-MI, the natural evolution of fibrosis in Gal-3 knockout mice was also affected. Our results suggest that Gal-3 is essential for wound healing because it regulates the dynamics of macrophage infiltration, proinflammatory and anti-inflammatory cytokine expression, and fibrosis along the temporal evolution of MI in mice. The deficit of Gal-3 affected the dynamics of wound healing, thus aggravating the evolution of remodeling and function.