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

Abstract

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-β (TGF-β), 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-β 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-β, 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.

Unraveling the role of galectin-3 in cardiac pathology and physiology

“…Recent studies showed that the absence of Gal-3 in aged mice exacerbates kidney fibrosis, oxidative stress, and promotes renal dysfunction, suggesting that Gal-3 may be protective for kidney aging ( Iacobini et al, 2005 ). We recently studied the cardiovascular phenotype of aged Gal-3 KO mice ( Fontana Estevez et al, 2022 ). At 2 years old, Gal-3 KO mice showed a significantly decreased in survival.…”

“…It is now well-established that Gal-3 plays a pivotal role in the development and progression of cardiovascular diseases, including heart failure (de Boer et al, 2018), atherosclerosis (Pusuroglu et al, 2017), hypertension (Gonzalez et al, 2014), myocarditis (Souza et al, 2017a;Kovacevic et al, 2018), and ischemic heart disease (Wan et al, 2022;Wang et al, 2023). Furthermore, recent findings emphasize the significant contribution of Gal-3 to the temporal evolution of cardiac and renal aging, suggesting a key role in the mechanisms associated with organ senescence (Iacobini et al, 2005;Fontana Estevez et al, 2022).…”

“…Galectin-3 is a multifunctional carbohydrate-binding protein involved in a range of physiological and pathological processes. In recent years, there has been growing attention from both clinical and basic investigators on the role of Gal-3 in the regulatory mechanisms associated with cardiovascular physiology ( Cassaglia et al, 2020 ; Fontana Estevez et al, 2022 ) and pathology ( Funasaka et al, 2014 ; Gonzalez et al, 2014 ; de Oliveira et al, 2015 ; Cassaglia et al, 2020 ). It is now well-established that Gal-3 plays a pivotal role in the development and progression of cardiovascular diseases, including heart failure ( de Boer et al, 2018 ), atherosclerosis ( Pusuroglu et al, 2017 ), hypertension ( Gonzalez et al, 2014 ), myocarditis ( Souza et al, 2017a ; Kovacevic et al, 2018 ), and ischemic heart disease ( Wan et al, 2022 ; Wang et al, 2023 ).…”

Metabolic Changes in Cardiac Aging

“…H19 acts as an inhibitor of competitive endogenous RNA (ceRNA) by secreting microRNA-19a (miR-19a) to regulate cytokine signaling expression, which subsequently leads to cardiac senescence by stimulating the p53/p21 signaling pathway, while H19 knockdown inhibits cardiomyocyte senescence [ 42 ]. Gal-3 is closely related to the regulation of cardiac remodeling, and the decreased expression of Gal-3 gene in the process of aging can aggravate cardiac hypertrophy, fibrosis and apoptosis, increase the expression of Ang II, matrix metalloproteinase-9 (MMP-9) and transforming growth factor (TGF- ), but decrease the expression of SIRT1 and sirtuin-7 (SIRT7) [ 43 ]. Ubiquitin endonuclease activity is also associated with age-related changes in the heart because genes involved in ubiquitin transfer are transcriptional up-regulated with age, which contributes to the induction of cardiomyocyte autophagy.…”