journal article
Open Access
Jun 01, 2020
Physiological cyclic stretch up-regulates angiotensin-converting enzyme 2 expression to reduce proliferation and migration of vascular smooth muscle cells
Abstract
Abstract
Angiotensin-converting enzyme 2 (ACE2) is considered as an endogenous negative regulator of renin–angiotensin system (RAS), exerting multiple cardiovascular protective roles. Whether mechanical stretch modulates ACE2 expression remains unknown. The present study aimed at investigating whether ACE2 is involved in physiological stretch (10% elongation, 1 Hz) mediated cellular functions and the underlying mechanism. Cultured human aortic smooth muscle cells (HASMCs) were exposed to 10% stretch for indicated time, and real-time PCR and Western blot analysis showed 10% stretch increased ACE2 expression and activity significantly compared with static conditions and increased Ang-(1-7) level, but decreased Ang II level; Brdu incorporation assay and Scratch test showed that ACE2 was involved in the inhibition of HASMCs proliferation and migration by 10% stretch; the Dual-Luciferase Reporter Assay demonstrated that 10% increased ACE2 promoter activity, but had no effect on ACE2 mRNA stability; kinase inhibition study and Electrophoretic mobility shift assay (EMSA) showed that JNK1/2 and PKCβII pathway, as well as their downstream transcription factors, AP-1 and NF-κB, were involved in 10% stretch induced ACE2 expression. In conclusion, our study indicates ACE2 is a mechanosensitive gene, and may represent a potential therapeutic target for mechanical forces related vascular diseases.
Angiotensin-converting enzyme 2 (ACE2) is considered as an endogenous negative regulator of renin–angiotensin system (RAS), exerting multiple cardiovascular protective roles. Whether mechanical stretch modulates ACE2 expression remains unknown. The present study aimed at investigating whether ACE2 is involved in physiological stretch (10% elongation, 1 Hz) mediated cellular functions and the underlying mechanism. Cultured human aortic smooth muscle cells (HASMCs) were exposed to 10% stretch for indicated time, and real-time PCR and Western blot analysis showed 10% stretch increased ACE2 expression and activity significantly compared with static conditions and increased Ang-(1-7) level, but decreased Ang II level; Brdu incorporation assay and Scratch test showed that ACE2 was involved in the inhibition of HASMCs proliferation and migration by 10% stretch; the Dual-Luciferase Reporter Assay demonstrated that 10% increased ACE2 promoter activity, but had no effect on ACE2 mRNA stability; kinase inhibition study and Electrophoretic mobility shift assay (EMSA) showed that JNK1/2 and PKCβII pathway, as well as their downstream transcription factors, AP-1 and NF-κB, were involved in 10% stretch induced ACE2 expression. In conclusion, our study indicates ACE2 is a mechanosensitive gene, and may represent a potential therapeutic target for mechanical forces related vascular diseases.
Topics
No keywords indexed for this article. Browse by subject →
References
41
[1]
Prado "Turbulent flow/low wall shear stress and stretch differentially affect aorta remodeling in rats" J. Hypertens. (2006) 10.1097/01.hjh.0000209987.51606.23
[2]
Qiu "Biomechanical regulation of vascular smooth muscle cell functions: from in vitro to in vivo understanding" J. R. Soc. Interface (2013) 10.1098/rsif.2013.0852
[3]
O'Rourke "Mechanical principles in arterial disease" Hypertension (1995) 10.1161/01.hyp.26.1.2
[4]
Anwar "The effect of pressure-induced mechanical stretch on vascular wall differential gene expression" J. Vasc. Res. (2012) 10.1159/000339151
[5]
Nehme "An Update on the Tissue Renin Angiotensin System and Its Role in Physiology and Pathology" J. Cardiovasc. Dev. Dis. (2019)
[6]
van Thiel "The renin-angiotensin system and its involvement in vascular disease" Eur. J. Pharmacol. (2015) 10.1016/j.ejphar.2015.03.090
[7]
Choi "Renin-angiotensin system blockade reduces cardiovascular events in nonheart failure, stable patients with prior coronary intervention" Coron. Artery Dis. (2018) 10.1097/mca.0000000000000609
[8]
Lin "Primary prevention of myocardial infarction with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in hypertensive patients with rheumatoid arthritis-A nationwide cohort study" PLoS ONE (2017) 10.1371/journal.pone.0188720
[9]
Varagic "ACE2: Angiotensin II/angiotensin-(1-7) balance in cardiac and renal injury" Curr. Hypertens. Rep. (2014) 10.1007/s11906-014-0420-5
[10]
De Mello "Local Renin Angiotensin Aldosterone Systems and Cardiovascular Diseases" Med. Clin. North Am. (2017) 10.1016/j.mcna.2016.08.017
[11]
Hong "Mechanical activation of angiotensin II type 1 receptors causes actin remodelling and myogenic responsiveness in skeletal muscle arterioles" J. Physiol. (2016) 10.1113/jp272834
[12]
Ito "Olmesartan inhibits cultured rat aortic smooth muscle cell death induced by cyclic mechanical stretch through the inhibition of the c-Jun N-terminal kinase and p38 signaling pathways" J. Pharmacol. Sci. (2015) 10.1016/j.jphs.2014.11.002
[13]
Chiu "Effects of cyclic stretch on the molecular regulation of myocardin in rat aortic vascular smooth muscle cells" J. Biomed. Sci. (2013) 10.1186/1423-0127-20-50
[14]
Liu "Mechanical stretch potentiates angiotensin II-induced proliferation in spontaneously hypertensive rat vascular smooth muscle cells" Hypertens. Res. (2010) 10.1038/hr.2010.187
[15]
Asanuma "Uniaxial strain upregulates matrix-degrading enzymes produced by human vascular smooth muscle cells" Am. J. Physiol. Heart Circ. Physiol. (2003) 10.1152/ajpheart.00494.2002
[16]
Mantella "Variability in vascular smooth muscle cell stretch-induced responses in 2D culture" Vasc. Cell (2015) 10.1186/s13221-015-0032-0
[17]
Wan "Involvement of BK channel in differentiation of vascular smooth muscle cells induced by mechanical stretch" Int. J. Biochem. Cell Biol. (2015) 10.1016/j.biocel.2014.11.011
[18]
Cheng "Mechanical stretch simulates proliferation of venous smooth muscle cells through activation of the insulin-like growth factor-1 receptor" Arterioscler. Thromb. Vasc. Biol. (2007) 10.1161/atvbaha.107.147371
[19]
Wang "Regulation of resistin by cyclic mechanical stretch in cultured rat vascular smooth muscle cells" Clin. Sci. (Lond.) (2009) 10.1042/cs20090155
[20]
Wang "Mechanoactivation of the angiotensin II type 1 receptor induces β-arrestin-biased signaling through Gαi coupling" J. Cell. Biochem. (2018) 10.1002/jcb.26552
[21]
Jiang "Identification of Amino Acid Residues in Angiotensin II Type 1 Receptor Sensing Mechanical Stretch and Function in Cardiomyocyte Hypertrophy" Cell. Physiol. Biochem. (2015) 10.1159/000430337
[22]
Hu "Mechanical stretch suppresses microRNA-145 expression by activating extracellular signal-regulated kinase 1/2 and upregulating angiotensin-converting enzyme to alter vascular smooth muscle cell phenotype" PLoS ONE (2014) 10.1371/journal.pone.0096338
[23]
Song "Upregulation of angiotensin converting enzyme 2 by shear stress reduced inflammation and proliferation in vascular endothelial cells" Biochem. Biophys. Res. Commun. (2020) 10.1016/j.bbrc.2020.02.151
[24]
Sahara "Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation" Cardiovasc. Res. (2014) 10.1093/cvr/cvt245
[25]
Song "Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways" Regul. Pept. (2013) 10.1016/j.regpep.2013.06.007
[26]
Zhang "Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells" Proc. Natl. Acad. Sci. U.S.A. (2010) 10.1073/pnas.1001253107
[27]
Tie "CCAAT/enhancer-binding protein β overexpression alleviates myocardial remodelling by regulating angiotensin-converting enzyme-2 expression in diabetes" J. Cell. Mol. Med. (2018) 10.1111/jcmm.13406
[28]
Lambert "Angiotensin-converting enzyme 2 is subject to post-transcriptional regulation by miR-421" Clin. Sci. (Lond.) (2014) 10.1042/cs20130420
[29]
Moran "Resveratrol Inhibits Growth of Experimental Abdominal Aortic Aneurysm Associated With Upregulation of Angiotensin-Converting Enzyme 2" Arterioscler. Thromb. Vasc. Biol. (2017) 10.1161/atvbaha.117.310129
[30]
Zhu "Activation of angiotensin II type 2 receptor suppresses TNF-α-induced ICAM-1 via NF-кB: possible role of ACE2" Am. J. Physiol. Heart Circ. Physiol. (2015) 10.1152/ajpheart.00814.2014
[31]
Deshotels "Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism" Hypertension (2014) 10.1161/hypertensionaha.114.03743
[32]
Moore "Laminar shear stress modulates phosphorylation and localization of RNA polymerase II on the endothelial nitric oxide synthase gene" Arterioscler. Thromb. Vasc. Biol. (2010) 10.1161/atvbaha.109.199554
[33]
Chen "Activation of p300 histone acetyltransferase activity is an early endothelial response to laminar shear stress and is essential for stimulation of endothelial nitric-oxide synthase mRNA transcription" J. Biol. Chem. (2008) 10.1074/jbc.m801803200
[34]
Hao "Angiotensin-Converting Enzyme 2 Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice" Hum Gene Ther. (2018) 10.1089/hum.2016.144
[35]
Li "Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways" Sci. Rep. (2016) 10.1038/srep27911
[36]
Li "Mechanical stress-activated PKCdelta regulates smooth muscle cell migration" FASEB J. (2003) 10.1096/fj.03-0150fje
[37]
Lavrentyev "High glucose-induced Nox1-derived superoxides downregulate PKC-βII, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs" Am. J. Physiol. Heart Circ. Physiol. (2009) 10.1152/ajpheart.00239.2008
[38]
Haga "Molecular basis of the effects of mechanical stretch on vascular smooth muscle cells" J. Biomech. (2007) 10.1016/j.jbiomech.2006.04.011
[39]
Ras/Rac-Dependent Activation of p38 Mitogen-Activated Protein Kinases in Smooth Muscle Cells Stimulated by Cyclic Strain Stress
Chaohong Li, Yanhua Hu, Gertraud Sturm et al.
Arteriosclerosis, Thrombosis, and Vascular Biology
2000
10.1161/01.atv.20.3.e1
[40]
Koka "Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway" Am. J. Pathol. (2008) 10.2353/ajpath.2008.070762
[41]
Kao "Cyclic Mechanical Stretch Up-regulates Hepatoma-Derived Growth Factor Expression in Cultured Rat Aortic Smooth Muscle Cells" Biosci. Rep. (2018) 10.1042/bsr20171398
Metrics
16
Citations
41
References
Details
- Published
- Jun 01, 2020
- Vol/Issue
- 40(6)
- License
- View
Authors
Cite This Article
Jiantao Song, Haiyan Qu, Bo Hu, et al. (2020). Physiological cyclic stretch up-regulates angiotensin-converting enzyme 2 expression to reduce proliferation and migration of vascular smooth muscle cells. Bioscience Reports, 40(6). https://doi.org/10.1042/bsr20192012
Related
You May Also Like
Apoptosis and apoptotic body: disease message and therapeutic target potentials
Xuebo Xu, Yueyang Lai · 2019
789 citations
Melittin: a Membrane-active Peptide with Diverse Functions
H. Raghuraman, Amitabha Chattopadhyay · 2007
561 citations
Single-molecule fluorescence microscopy review: shedding new light on old problems
Sviatlana Shashkova, Mark C. Leake · 2017
269 citations
Epithelial–mesenchymal transition and its transcription factors
Pallabi Debnath, Rohit Singh Huirem · 2021
242 citations
Infrared spectroscopic studies of biomembranes and model membranes
David C. Lee, Dennis Chapman · 1986
123 citations