Fontana Estevez Florencia Sofia, Betazza Maria Celeste, Miksztowicz Verónica, Seropian Ignacio Miguel, Silva Mauro Gastón, Penas Federico, Touceda Vanessa, Selser Carolina, Villaverde Alejo, Goren Nora, Cianciulli Tomás Francisco, Medina Vanina, Morales Celina, Gironacci Mariela, González Germán Esteban
Pontificia Universidad Católica Argentina, Facultad de Medicina, Instituto de Investigaciones Biomédicas UCA-CONICET, Laboratorio de Patología Cardiovascular Experimental e Hipertensión Arterial, Buenos Aires, Argentina.
Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Bioquímica General y Bucal, Buenos Aires, Argentina.
Cell Physiol Biochem. 2022 Aug 12;56(4):353-366. doi: 10.33594/000000556.
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.
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.
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.
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.
背景/目的：衰老伴随着以心肌肥大、纤维化和功能障碍为特征的进行性不良心脏重塑。我们之前报道过，半乳糖凝集素-3（Gal-3）是与高血压性心脏病和心肌梗死相关的炎症和纤维化的关键调节因子。然而，Gal-3在与年龄相关的心脏重塑中的作用和机制此前尚未得到研究。我们假设Gal-3在心脏衰老中起关键作用，其缺乏会加剧心肌肥大和纤维化的潜在机制。
研究24月龄的雄性C57BL/6（对照）（n = 24）和Gal-3基因敲除（KO）（n = 29）小鼠，以评估Gal-3在心脏衰老中的作用。我们评估了：1）存活率；2）通过体积描记法测量收缩压（SBP）；3）通过组织学和免疫组织化学分析的定量评估心肌肥大、细胞凋亡和纤维化；4）通过放射免疫测定法检测心脏中血管紧张素（Ang）II、Ang（1 - 7）的表达；5）通过RT-qPCR检测转化生长因子-β（TGF-β）、沉默调节蛋白（SIRT）1、SIRT7和基质金属蛋白酶9（MMP-9）；6）通过超声心动图检测心室重塑和功能。
我们发现老年Gal-3基因敲除小鼠的存活率较低，并且表现出加剧的心肌肥大和纤维化，而SBP没有变化。同样，与对照组相比，Gal-3基因敲除小鼠心脏中的心肌细胞凋亡和MMP-9 mRNA表达显著增加。此外，老年Gal-3基因敲除小鼠心脏中的Ang II和TGF-β表达较高，而SIRT1和SIRT7表达降低。
我们的研究结果强烈表明，Gal-3通过调节与病理性肥大发展相关的关键机制参与与年龄相关的心脏重塑。Gal-3基因缺失缩短了寿命，并显著增加了与年龄相关的心肌肥大、细胞凋亡和纤维化机制，包括Ang-II、TGF-β和MMP-9。同时，心脏特异性SIRT1和SIRT7的表达减少，而它们与延缓年龄依赖性心肌病密切相关。
