Endothelial Klf2-Foxp1-TGFβ signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling

被引：32

作者：

Li, Hongda ^{[1
]}

Wang, Yanfang ^{[1
]}

Liu, Jiwen ^{[1
]}

Chen, Xiaoli ^{[1
]}

Duan, Yunhao ^{[1
]}

Wang, Xiaoyu ^{[1
]}

Shen, Yajing ^{[3
]}

Kuang, Yashu ^{[1
]}

Zhuang, Tao ^{[1
]}

Tomlinson, Brain ^{[4
]}

Chan, Paul ^{[5
]}

Yu, Zuoren ^{[1
]}

Cheng, Yu ^{[3
]}

Zhang, Lin ^{[1
]}

Liu, Zhongmin ^{[1
]}

Zhang, Yuzhen ^{[1
]}

Zhao, Zhenlin ^{[6
]}

Zhang, Qi ^{[2
]}

Liu, Jie ^{[1
,6
]}

机构：

[1] Tongji Univ, Shanghai East Hosp, Sch Med, Res Ctr Translat Med,Minist Educ China,Key Lab Ar, 150 Jimo Rd, Shanghai 200120, Peoples R China

[2] Tongji Univ, Shanghai East Hosp, Dept Cardiol, Sch Med, 150 Jimo Rd, Shanghai 200120, Peoples R China

[3] Tongji Univ, Inst Biomed Engn & Nano Sci, Sch Med, Shanghai, Peoples R China

[4] Macau Univ Sci & Technol, Fac Med, Macau, Peoples R China

[5] Taipei Med Univ, Wan Fang Hosp, Dept Internal Med, Div Cardiol, Taipei, Taiwan

[6] Shenzhen Ruipuxun Acad Stem Cell & Regenerat Med, 14 Jinhui Rd, Shenzhen 518122, Peoples R China

来源：

THERANOSTICS | 2021年 / 11卷 / 04期

基金：

中国国家自然科学基金;

关键词：

Heart failure (HF); Maladaptive cardiac remodeling (cardiac fibrosis and hypertrophy); HMG-CoA reductase inhibitors; Simvastatin; Vascular endothelial cells (ECs); Kruppel-like Factor 2 (Klf2); Transforming growth factor-beta 1 (TGF beta 1); Forkhead Box P1 (Foxp1); HEART-FAILURE; PRESSURE-OVERLOAD; FIBROSIS; HYPERTROPHY; STATINS; EXPRESSION; PATHWAY; CELLS;

D O I：

10.7150/thno.48153

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Aims: Pathological cardiac fibrosis and hypertrophy are common features of left ventricular remodeling that often progress to heart failure (HF). Endothelial cells (ECs) are the most abundant non-myocyte cells in adult mouse heart. Simvastatin, a strong inducer of Kruppel-like Factor 2 (Klf2) in ECs, ameliorates pressure overload induced maladaptive cardiac remodeling and dysfunction. This study aims to explore the detailed molecular mechanisms of the anti-remodeling effects of simvastatin. Methods and Results: RGD-magnetic-nanoparticles were used to endothelial specific delivery of siRNA and we found absence of simvastatin's protective effect on pressure overload induced maladaptive cardiac remodeling and dysfunction after in vivo inhibition of EC-Klf2. Mechanism studies showed that EC-Klf2 inhibition reversed the simvastatin-mediated reduction of fibroblast proliferation and myofibroblast formation, as well as cardiomyocyte size and cardiac hypertrophic genes, which suggested that EC-Klf2 might mediate the anti-fibrotic and anti-hypertrophy effects of simvastatin. Similar effects were observed after Klf2 inhibition in cultured ECs. Moreover, Klf2 regulated its direct target gene TGF beta 1 in ECs and mediated the protective effects of simvastatin, and inhibition of EC-Klf2 increased the expression of EC-TGF beta 1 leading to simvastatin losing its protective effects. Also, EC-Klf2 was found to regulate EC-Foxp1 and loss of EC-Foxp1 attenuated the protective effects of simvastatin similar to EC-Klf2 inhibition. Conclusions: We conclude that cardiac microvasculature ECs are important in the modulation of pressure overload induced maladaptive cardiac remodeling and dysfunction, and the endothelial Klf2-TGF beta 1 or Klf2-Foxp1-TGF beta 1 pathway mediates the preventive effects of simvastatin. This study demonstrates a novel mechanism of the non-cholesterol lowering effects of simvastatin for HF prevention.

引用

页码：1609 / 1625

页数：17

共 42 条

[1] The effects of cholesterol lowering with simvastatin on cause-specific mortality and on cancer incidence in 20,536 high-risk people: a randomised placebo-controlled trial [ISRCTN48489393]
Armitage, Jane
Collins, Rory
Bowman, Louise
Parish, Sarah
Sleight, Peter
Peto, Richard
Meade, T.
Youngman, L.
Buxton, M.
de Bono, D.
George, C.
Fuller, J.
Keech, A.
Mansfield, A.
Pentecost, B.
Simpson, D.
Warlow, C.
McNamara, J.
O'Toole, L.
Doll, R.
Wilhelmsen, L.
Fox, K. M.
Hill, C.
Sandercock, P.
[J]. BMC MEDICINE, 2005, 3 (1)
[2] KLF2 suppresses TGF-β signaling in endothelium through induction of Smad7 and inhibition of AP-1
Boon, Reinier A.
Fledderus, Joost O.
Volger, Oscar L.
van Wanrooij, Eva J. A.
Pardali, Evangelia
Weesie, Frank
Kuiper, Johan
Pannekoek, Hans
ten Dijke, Peter
Horrevoets, Anton J. G.
[J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2007, 27 (03) : 532 - 539
[3] Trends in Hospitalizations and Survival of Acute Decompensated Heart Failure in Four US Communities (2005-2014): ARIC Study Community Surveillance
Chang, Patricia P.
Wruck, Lisa M.
Shahar, Eyal
Rossi, Joseph S.
Loehr, Laura R.
Russell, Stuart D.
Agarwal, Sunil K.
Konety, Suma H.
Rodriguez, Carlos J.
Rosamond, Wayne D.
[J]. CIRCULATION, 2018, 138 (01) : 12 - 24
[4] ANGIOTENSIN-II INDUCES TGF-BETA-1 PRODUCTION IN RAT-HEART ENDOTHELIAL-CELLS
CHUA, CC
DIGLIO, CA
SIU, BB
CHUA, BHL
[J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1994, 1223 (01): : 141 - 147
[5] Collins R, 2002, LANCET, V360, P7, DOI 10.1016/S0140-6736(02)09327-3
[6] KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium
Dekker, Rob J.
Boon, Reinier A.
Rondaij, Mariska G.
Kragt, Astrid
Volger, Oscar L.
Elderkamp, Yvonne W.
Meijers, Joost C. M.
Voorberg, Jan
Pannekoek, Hans
Horrevoets, Anton J. G.
[J]. BLOOD, 2006, 107 (11) : 4354 - 4363
[7] A general strategy for isolation of endothelial cells from murine tissues - Characterization of two endothelial cell lines from the murine lung and subcutaneous sponge implants
Dong, QG
Bernasconi, S
Lostaglio, S
DeCalmanovici, RW
MartinPadura, I
Breviario, F
Garlanda, C
Ramponi, S
Mantovani, A
Vecchi, A
[J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1997, 17 (08) : 1599 - 1604
[8] Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells
Dong, Weijiang
Vuletic, Simona
Albers, John J.
[J]. JOURNAL OF LIPID RESEARCH, 2009, 50 (10) : 2095 - 2102
[9] Gao Shumin, 2011, Curr Protoc Mouse Biol, V1, P71
[10] Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation
Haudek, Sandra B.
Gupta, Damon
Dewald, Oliver
Schwartz, Robert J.
Wei, Lei
Trial, JoAnn
Entman, Mark L.
[J]. CARDIOVASCULAR RESEARCH, 2009, 83 (03) : 511 - 518

← 1 2 3 4 5 →