Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Background: Heart failure is one of the leading causes of death in the world, and cardiac hypertrophy is one of the major pathogeneses of heart failure. In cardiac hypertrophy, cardiomyocytes die because of various stimuli, and these dead cells are supposed to be promptly engulfed by phagocytic cells. However, the cells and molecules responsible for removing dead cardiomyocytes in cardiac hypertrophy have not yet been revealed. In the current study, we investigated the molecular mechanism responsible for removing dead cells in cardiac hypertrophy.
Method: Transverse Aortic Constriction (TAC) operation was performed on six- to eight-week-old male C57BL/6J wild-type (WT) mice and MFG-E8 knockout (KO) mice to generate mouse models of cardiac hypertrophy. Cardiac function and pathological conditions of the TAC-operated heart were evaluated using echocardiography and real time RT-PCR.
Results: To identify the molecules responsible for clearing dead cells in cardiac hypertrophy, we searched the engulfment-related proteins that showed an increase in expression levels. Of the several molecules tested, the expression level of MFG-E8, a molecule that promotes engulfment, in the heart was significantly increased after TAC operation. MFG-E8 was specifically expressed in cardiac myofibroblasts that appear during cardiac hypertrophy. Immunohistochemical analysis revealed that cardiac myofibroblasts have the ability to engulf dead cells. Therefore, more unengulfed dead cells remained in TAC-operated hearts of MFG-E8 KO mice than in those of WT mice. Consistent with these results, the excessive inflammation and its resultant fibrosis were observed in the hypertrophic hearts of MFG-E8 KO mice. The cardiac functions of TAC-operated MFG-E8 KO mice were markedly worse compared with those of TAC-operated WT mice. In addition, exogenous expression of MFG-E8 in hearts of WT mice by the adeno-associated virus significantly improved the cardiac function after TAC operation.
Conclusion: First, we identified the cells and molecules responsible for the removal of dead cardiomyocytes in cardiac hypertrophy. Further, we found that the enhancement of removal of dead cells in hypertrophic hearts by treatment with MFG-E8 significantly improves the condition of the hearts.
