Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA 4-Dependent CCN 1 Secretion.

Abstract

Background Stress-induced cell premature senescence participates in a variety of tissue and organ remodeling by secreting such proteins as proinflammatory cytokines, chemokines, and growth factors. However, the role of cardiomyocyte senescence in heart remodeling after acute myocardial infarction has not been thoroughly elucidated to date. Therefore, we sought to clarify the impact of premature myocardial senescence on postinfarction heart function. Methods and Results Senescence markers, including p16 INK4a, p21 CIP1/WAF1, and SA -β-gal staining, were analyzed in several heart disease models by immunostaining. Both postinfarction mouse hearts and ischemic human myocardium demonstrated increased senescence markers. Additionally, senescence-related secretory phenotype was activated after acute myocardial infarction, which upregulated senescence-related secretory phenotype factors, including CCN family member 1 ( CCN 1), interleukin-1α, tumor necrosis factor α, and monocyte chemoattractant protein-1. In vivo, a tail vein injection of AAV 9- Gata4-sh RNA significantly attenuated senescence-related secretory phenotype secretion and aggravated postinfarction heart dysfunction. Furthermore, among activated senescence-related secretory phenotype factors, CCN 1 administration reduced myofibroblast viability in vitro and rescued the deleterious effect of AAV 9- Gata4-sh RNA in vivo. Conclusions Myocardial premature senescence was observed in the ischemic hearts and improved postinfarction heart function, partly through the GATA-binding factor 4- CCN 1 pathway.

• Authors: Sumei Cui, Li Xue, Feihong Yang, Shuai Dai, Ziqi Han, Kai Liu, Baoshan Liu, Qiuhuan Yuan, Zhaoqiang Cui, Yun Zhang, Feng Xu, Yuguo Chen
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 7 Issue 18 Pg. e009111 (09 18 2018) ISSN: 2047-9980 [Electronic] England
• PMID: 30371213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCN1 protein, mouse
• Cysteine-Rich Protein 61
• GATA4 Transcription Factor
• Gata4 protein, mouse

Topics

• Animals
• Blotting, Western
• Cells, Cultured
• Cellular Senescence (physiology)
• Cysteine-Rich Protein 61 (metabolism)
• Disease Models, Animal
• GATA4 Transcription Factor (metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (metabolism, pathology)
• Myocytes, Cardiac (cytology, metabolism)