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ORIGINAL ARTICLE
Year : 2018  |  Volume : 131  |  Issue : 19  |  Page : 2302-2309

Cardiac Fibroblast-Specific Activating Transcription Factor 3 Promotes Myocardial Repair after Myocardial Infarction


Key Laboratory of Remodeling-Related Cardiovascular Disease (Ministry of Education), Beijing Anzhen Hospital Affiliated to Captital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029, China

Correspondence Address:
Dr. Yu-Lin Li
Beijing Institute of Heart, Lung and Blood Vessel Diseases, Anzhen Hospital, Capital Medical University, Beijing 100029
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.241794

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Background: Myocardial ischemia injury is one of the leading causes of death and disability worldwide. Cardiac fibroblasts (CFs) have central roles in modulating cardiac function under pathophysiological conditions. Activating transcription factor 3 (ATF3) plays a self-protective role in counteracting CF dysfunction. However, the precise function of CF-specific ATF3 during myocardial infarction (MI) injury/repair remains incompletely understood. The aim of this study was to determine whether CF-specific ATF3 affected cardiac repair after MI. Methods: Fifteen male C57BL/6 wild-type mice were performed with MI operation to observe the expression of ATF3 at 0, 0.5, 1.0, 3.0, and 7.0 days postoperation. Model for MI was constructed in ATF3TGfl/flCol1a2-Cre+ (CF-specific ATF3 overexpression group, n = 5) and ATF3TGfl/flCol1a2-Cre− male mice (without CF-specific ATF3 overexpression group, n = 5). In addition, five mice of ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre− were subjected to sham MI operation. Heart function was detected by ultrasound and left ventricular remodeling was observed by Masson staining (myocardial fibrosis area was detected by blue collagen deposition area) at the 28th day after MI surgery in ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre− mice received sham or MI operation. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect cell proliferation/cell cycle-related gene expression in cardiac tissue. BrdU staining was used to detect fibroblast proliferation. Results: After establishment of an MI model, we found that ATF3 proteins were increased in the heart of mice after MI surgery and dominantly expressed in CFs. Genetic overexpression of ATF3 in CFs (ATF3TGfl/flCol1a2-Cre+ group) resulted in an improvement in the heart function as indicated by increased cardiac ejection fraction (41.0% vs. 30.5%, t = 8.610, P = 0.001) and increased fractional shortening (26.8% vs. 18.1%, t = 7.173, P = 0.002), which was accompanied by a decrease in cardiac scar area (23.1% vs. 11.0%, t = 8.610, P = 0.001). qRT-PCR analysis of CFs isolated from ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre− ischemic hearts revealed a distinct transcriptional profile in ATF3-overexpressing CFs, displaying pro-proliferation properties. BrdU-positive cells significantly increased in ATF3-overexpressing CFs than control CFs under angiotensin II stimuli (11.5% vs. 6.8%, t = 31.599, P = 0.001) or serum stimuli (31.6% vs. 20.1%, t = 31.599, P = 0.001). The 5(6)-carboxyfluorescein N-hydroxysuccinimidyl ester assay showed that the cell numbers of the P2 and P3 generations were higher in the ATF3-overexpressing CFs at 24 h (P2: 91.6% vs. 71.8%, t = 8.465, P = 0.015) and 48 h (P3: 81.6% vs. 51.1%, t = 9.029, P = 0.012) after serum stimulation. Notably, ATF3 overexpression-induced CF proliferation was clearly increased in the heart after MI injury. Conclusions: We identify that CF-specific ATF3 might contribute to be MI repair through upregulating the expression of cell cycle/proliferation-related genes and enhancing cell proliferation.

 

 Abstract in Chinese

ATF3通过促进成纤维细胞增殖抑制心肌梗死后心肌损伤

摘要

目的:心肌梗死是全球心血管死亡的首要病因。成纤维细胞调节生理和病理刺激下心脏功能变化。ATF3是保护性转录因子参与成纤维细胞的功能调控。但是成纤维细胞特异性ATF3在心梗损伤/修复中的机制还不清楚。

方法:15只雄性C57BL/6野生小鼠分别行冠脉左前降支结扎手术观察ATF3的表达和定位情况,选取我们前期构建的成纤维细胞特异性ATF3过表达小鼠(ATF3TGfl/flCol1a2-Cre+)及对照组小鼠(ATF3TGfl/flCol1a2-Cre-)各10只,对其进行心肌梗死手术及假手术处理,在术后第28 天,采用超声检测心功能、Masson染色观察左心室重塑情况。采用qRT-PCR检测心脏组织中细胞增殖/细胞周期相关基因表达及采用BrdU染色检测心脏中细胞增殖。

结果:与术前相比,心肌梗死手术后ATF3表达升高,并且高表达在成纤维细胞。与ATF3TGfl/flCol1a2-Cre-对比,在心肌梗死术后28d, ATF3TGfl/flCol1a2-Cre+的心功能明显改善(EF: 41 % vs. 30.5%, t=8.610, P=0.001; FS 26.8% vs. 18.1%, t=7.173, P=0.002),左心室纤维化面积明显降低(左心室瘢痕面积: 23.1% vs.11.0 %, t=8.610, P=0.001)。RT-PCR检测显示小鼠心脏组织中细胞增殖/细胞周期相关基因表达增加。BrdU染色检测显示ATF3过表达成纤维细胞的增殖在血管紧张素II刺激(11.5% vs 6.8%, t=31.599,P=0.001)和血清刺激(31.6% vs. 20.1%, t = 31.599, P=0.001) 明显高于野生型成纤维细胞。CFSE检测显示ATF3过表达成纤维细胞增殖能力在血清刺激后24小时(P2: 91.6% vs. 71.8%, t=8.645, P=0.015)和48小时(P3: 81.6% vs. 51.1%, t=9.029, P=0.012)都明显高于野生成纤维细胞。成纤维细胞特异性过表达ATF3小鼠心梗后心脏中成纤维细胞的增殖高于对照小鼠。

结论ATF3可能通过促进成纤维细胞增殖抑制心肌梗死后心肌损伤。



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