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Genetic Deletion of Galectin-3 Exacerbates Age-Related Myocardial Hypertrophy and Fibrosis in Mice
Florencia Sofia Fontana Estevez1, Maria Celeste Betazza1, Verónica Miksztowicz1,2
1Pontificia Universidad Católica Argentina, Facultad de Medicina, Instituto de Investigaciones Biomédicas UCA-CONICET, Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina.
Insights
Galectin-3 (Gal-3) deficiency worsens cardiac aging, increasing myocardial hypertrophy, fibrosis, and apoptosis. This study reveals Gal-3’s role in age-related cardiac remodeling and reduced lifespan in mice.
Area of Science:
- Cardiovascular Research
- Aging Biology
- Molecular Cardiology
Background:
- Aging causes detrimental cardiac remodeling, including hypertrophy, fibrosis, and dysfunction.
- Galectin-3 (Gal-3) is implicated in inflammation and fibrosis in heart disease.
- The specific role of Gal-3 in age-related cardiac remodeling remains unexplored.
Purpose of the Study:
- To investigate the role and mechanism of Gal-3 in age-related cardiac remodeling.
- To test the hypothesis that Gal-3 deficiency exacerbates myocardial hypertrophy and fibrosis during aging.
Main Methods:
- Studied aged (24-month-old) male C57BL/6 control and Gal-3 knockout (KO) mice.
- Assessed survival rates, systolic blood pressure, cardiac hypertrophy, apoptosis, and fibrosis.
- Quantified cardiac expression of Angiotensin II, Ang (1-7), TGF-β, SIRT1, SIRT7, and MMP-9.
Main Results:
- Aged Gal-3 KO mice exhibited lower survival rates and worsened myocardial hypertrophy and fibrosis.
- Increased myocardial apoptosis and MMP-9 mRNA expression were observed in Gal-3 KO mice.
- Gal-3 KO mice showed elevated cardiac Ang II and TGF-β, with reduced SIRT1 and SIRT7 expression.
Conclusions:
- Gal-3 plays a significant role in age-related cardiac remodeling.
- Gal-3 deficiency accelerates cardiac aging, increasing hypertrophy, apoptosis, and fibrosis.
- Gal-3 influences age-dependent pathways involving Ang-II, TGF-β, MMP-9, SIRT1, and SIRT7 in the heart.
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.
