Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure-Overload in Mice

Abstract

BackgroundBasigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinase and promotes inflammation.Methods and ResultsWe performed transverse aortic constriction (TAC) in Bsg+/− and wild-type (WT) mice, and thereafter examined the time-course for 4 weeks. Bsg+/+ mice showed significantly less cardiac fibrosis compared with WT mice after TAC. Both metalloproteinase activities and oxidative stress in loaded LV were significantly less in Bsg+/− mice compared with WT mice. Echocardiography revealed that Bsg+/− mice showed less hypertrophy and preserved LV function compared with WT mice. Consistently, Bsg+/− mice showed better survival compared with Bsg+/+ mice, regardless of the source of bone marrow (Bsg+/+ or Bsg+/−). Conversely, cardiac-specific Bsg overexpression mice showed significantly poor survival as compared with littermate controls. Next, we isolated cardiac fibroblasts (CFs) and examined their responses to angiotensin-II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion and ERK/Akt/JNK activities in Bsg+/+ CFs, which were significantly less in Bsg+/− CFs. Recombinant Bsg promoted ERK/Akt activities in CFs. Consistently, Bsg+/− CFs were significantly less proliferative compared with Bsg+/+ CFs. In the clinical study, serum levels of soluble Bsg (sBsg) were significantly elevated in patients with heart failure compared with healthy controls, significantly associated with poor prognosis.ConclusionsBsg plays a crucial role in the pathogenesis of cardiac hypertrophy, fibrosis and failure in mice and humans. BackgroundBasigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinase and promotes inflammation. Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinase and promotes inflammation. Methods and ResultsWe performed transverse aortic constriction (TAC) in Bsg+/− and wild-type (WT) mice, and thereafter examined the time-course for 4 weeks. Bsg+/+ mice showed significantly less cardiac fibrosis compared with WT mice after TAC. Both metalloproteinase activities and oxidative stress in loaded LV were significantly less in Bsg+/− mice compared with WT mice. Echocardiography revealed that Bsg+/− mice showed less hypertrophy and preserved LV function compared with WT mice. Consistently, Bsg+/− mice showed better survival compared with Bsg+/+ mice, regardless of the source of bone marrow (Bsg+/+ or Bsg+/−). Conversely, cardiac-specific Bsg overexpression mice showed significantly poor survival as compared with littermate controls. Next, we isolated cardiac fibroblasts (CFs) and examined their responses to angiotensin-II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion and ERK/Akt/JNK activities in Bsg+/+ CFs, which were significantly less in Bsg+/− CFs. Recombinant Bsg promoted ERK/Akt activities in CFs. Consistently, Bsg+/− CFs were significantly less proliferative compared with Bsg+/+ CFs. In the clinical study, serum levels of soluble Bsg (sBsg) were significantly elevated in patients with heart failure compared with healthy controls, significantly associated with poor prognosis. We performed transverse aortic constriction (TAC) in Bsg+/− and wild-type (WT) mice, and thereafter examined the time-course for 4 weeks. Bsg+/+ mice showed significantly less cardiac fibrosis compared with WT mice after TAC. Both metalloproteinase activities and oxidative stress in loaded LV were significantly less in Bsg+/− mice compared with WT mice. Echocardiography revealed that Bsg+/− mice showed less hypertrophy and preserved LV function compared with WT mice. Consistently, Bsg+/− mice showed better survival compared with Bsg+/+ mice, regardless of the source of bone marrow (Bsg+/+ or Bsg+/−). Conversely, cardiac-specific Bsg overexpression mice showed significantly poor survival as compared with littermate controls. Next, we isolated cardiac fibroblasts (CFs) and examined their responses to angiotensin-II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion and ERK/Akt/JNK activities in Bsg+/+ CFs, which were significantly less in Bsg+/− CFs. Recombinant Bsg promoted ERK/Akt activities in CFs. Consistently, Bsg+/− CFs were significantly less proliferative compared with Bsg+/+ CFs. In the clinical study, serum levels of soluble Bsg (sBsg) were significantly elevated in patients with heart failure compared with healthy controls, significantly associated with poor prognosis. ConclusionsBsg plays a crucial role in the pathogenesis of cardiac hypertrophy, fibrosis and failure in mice and humans. Bsg plays a crucial role in the pathogenesis of cardiac hypertrophy, fibrosis and failure in mice and humans.