Abstract 12745: Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure-Overload in Mice
Background: Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinases (MMPs), promotes inflammation and is strongly expressed in cardiac tissues of patients with dilated cardiomyopathy. However, the role of Bsg in the pathogenesis of cardiac hypertrophy and failure remains to be elucidated.
Methods and Results: We performed transverse aortic constriction (TAC) in wild-type (WT) mice, and thereafter examined the time-course for 4 weeks. Importantly, Bsg expression was enhanced in the left ventricle (LV) after TAC in a time-dependent manner. To further elucidate the roles of Bsg, we examined whether cardiac responses to chronic pressure-overload were ameliorated in Bsg+/- mice. Echocardiography revealed that Bsg+/- mice showed less hypertrophy (P<0.05), less LV end-diastolic diameter (P<0.01), and preserved LV fractional shortening (35.32±1.60 vs. 23.32±0.89 %, P<0.01) compared with littermate controls after TAC (n=8 each). In addition, Bsg+/- mice showed significantly less LV weight/body weight ratio (P<0.05) and lung weight/body weight ratio (P<0.01) compared with controls. Both MMP activities (in situ zymography by DQ gelatin) and oxidative stress (dihydroethidium staining) in loaded LV were less in Bsg+/- mice compared with controls. Bsg+/- mice were more likely to survive after TAC compared with Bsg+/+ mice, regardless of the source of bone marrow (Bsg+/+ or Bsg+/-), suggesting the crucial role of Bsg in cardiac tissues. Importantly, histological analysis showed that cardiac interstitial fibrosis was remarkably less in Bsg+/- mice compared with controls (5.08±1.23 vs. 12.25±1.17 %, P<0.01). Finally, we isolated cardiac fibroblasts (CFs) from Bsg+/+ and Bsg+/- mice, which were subjected to stimulation with angiotensin II (100nM) or cyclic mechanical stretch (+20%). Both stimuli significantly increased Bsg expression, secretion, and ERK/Akt activation in Bsg+/+ CFs, all of which were significantly less in Bsg+/- CFs (all P<0.05). Consistently, Bsg+/- CFs were significantly less proliferative compared with Bsg+/+ CFs.
Conclusions: These results indicate that Bsg plays a crucial role in the pressure-overload-induced cardiac hypertrophy, fibrosis and failure in mice.
Author Disclosures: K. Suzuki: None. K. Satoh: None. I. Shohei: None. K. Kadomatsu: None. H. Shimokawa: None.
- © 2014 by American Heart Association, Inc.