MicroRNAs e células-tronco mesenquimais: esperança para a hipertensão pulmonar

Zhu, Zhaowei; Fang, Zhenfei; Hu, Xinqun; Zhou, Shenghua

doi:10.5935/1678-9741.20150033

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Brazilian Journal of Cardiovascular Surgery

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Sumário

REVIEW ARTICLE • Rev Bras Cir Cardiovasc 30 (3) • Jul-Sep 2015 • https://doi.org/10.5935/1678-9741.20150033 copiar

MicroRNAs e células-tronco mesenquimais: esperança para a hipertensão pulmonar

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

A hipertensão pulmonar é uma doença devastadora e refratária, para a qual não existe cura. Recentemente, microRNAs e células-tronco mesenquimais emergiram como novos métodos para tratar a hipertensão pulmonar. Mais de 20 tipos de microRNAs podem participar no processo de hipertensão pulmonar. Ao que parece, microRNAs ou células-tronco mesenquimais podem atenuar alguns sintomas de hipertensão pulmonar em animais de e até mesmo melhorar a função cardíaca e do pulmão durante a hipertensão pulmonar. No entanto, a relação entre células-tronco mesenquimais, microRNAs e hipertensão pulmonar não é clara. E os mecanismos subjacentes a sua função ainda precisam ser investigados. Neste estudo, revisamos as descobertas recentes no tratamento da hipertensão pulmonar baseado em células-tronco mesenquimais e microRNAs, enfocando o papel potencial dos microRNAs para regular as células-tronco mesenquimais na hipertensão pulmonar e o papel dos exossomos entre células-tronco mesenquimais e hipertensão pulmonar.

Descritores
Hipertensão Pulmonar; MicroRNAs; Transplante de Células-Tronco Mesenquimais

Abbreviations, acronyms & symbols
BMPR2	Bone morphogenetic protein receptor type II
BMSCs	Bone marrow stromal cells
CTEPH	Chronic thromboembolic pulmonary hypertension
HGF	Hepatocyte growth factor
IGF	Insulin-like growth factor
MSCs	Mesenchymal stem cells
PH	Pulmonary hypertension
RV	Right ventricle

microRNAs	Expression in PH	Research object	Function in PH	Mechanisms	References
MiR-22	reduced	animal	unknow	unknow	²⁵25 Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716-23.
miR-30	reduced	animal	unknow	unknow	²⁵25 Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716-23.
let-7f	reduced	animal	unknow	unknow	²⁵25 Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716-23.
miR-21	reduced	animal and human	unknow	unknow	²⁵25 Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716-23.
let-7a	reduced	animal	unknow	unknow	²⁵25 Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716-23.
miR-150	reduced	human	protect	unknow	²⁷27 Rhodes CJ, Wharton J, Boon RA, Roexe T, Tsang H, Wojciak-Stothard B, et al. Reduced miR-150 is associated with poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187(3):294-302.
miR-204	reduced	animal and human	protect	target SHP2, inhibit PASMCs proliferation	²⁶26 Courboulin A, Paulin R, Giguère NJ, Saksouk N, Perreault T, Meloche J, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208(3):535-48.
miR-322	increased	animal	unknow	unknow	²⁵25 Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716-23.
miR-451	increased	animal	unknow	unknow	²⁵25 Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30(4):716-23.
miR-210	increased	animal	impair	Antiapoptotic effect in PASMCs	²⁹29 Gou D, Ramchandran R, Peng X, Yao L, Kang K, Sarkar J, et al. miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia. Am J Physiol Lung Cell Mol Physiol. 2012;303(8):L682-91.
miR-21	increased	animal	impair	Enhanced the proliferation of human PASMCs	³¹31 Yang S, Banerjee S, Freitas Ad, Cui H, Xie N, Abraham E, et al. miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol. 2012;302(6):L521-9. ^, ³²32 Parikh VN, Jin RC, Rabello S, Gulbahce N, White K, Hale A, et al. MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation. 2012;125(12):1520-32.
miR-759	increased	human	protect	Decrease the amount of total FGA mRNA via affecting the stability of FGA long isoform (aE) mRNA, which can contribute to CTEPH.	³⁵35 Chen Z, Nakajima T, Tanabe N, Hinohara K, Sakao S, Kasahara Y, et al. Susceptibility to chronic thromboembolic pulmonary hypertension may be conferred by miR-759 via its targeted interaction with polymorphic fibrinogen alpha gene. Hum Genet. 2010;128(4):443-52.

miR-17/92, 20a	increased	animal	impair	STAT3-miR-17/92-BMPR2 pathway	³⁷37 Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M, et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res. 2009;104(10):1184-91. ^, ⁴⁰40 Brock M, Samillan VJ, Trenkmann M, Schwarzwald C, Ulrich S, Gay RE, et al. AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur Heart J. 2014;35(45):3203-11.
miR-145	incerased	animal and human	impair	Inhibit the BMPR2 function	³⁸38 Davis-Dusenbery BN, Chan MC, Reno KE, Weisman AS, Layne MD, Lagna G, et al. down-regulation of Kruppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-beta and bone morphogenetic protein 4. J Biol Chem. 2011;286(32):28097-110. ^, ³⁹39 Caruso P, Dempsie Y, Stevens HC, McDonald RA, Long L, Lu R, et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res. 2012;111(3):290-300.
miR-143	increased	animal and human	impair	Prevents down-regulation of KLF4 and activation of contractile genes by TGF-P or BMP4	³⁸38 Davis-Dusenbery BN, Chan MC, Reno KE, Weisman AS, Layne MD, Lagna G, et al. down-regulation of Kruppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-beta and bone morphogenetic protein 4. J Biol Chem. 2011;286(32):28097-110.
miR-17	increased	animal	impair	up-regulation of p21	⁴¹41 Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med. 2012;185(4):409-19.
miR-206	decreased	animal	protect	down regulating Notch-3	⁴³43 Jalali S, Ramanathan GK, Parthasarathy PT, Aljubran S, Galam L, Yunus A, et al. Mir-206 regulates pulmonary artery smooth muscle cell proliferation and differentiation. PLoS One. 2012;7(10):e46808.
miR-328	decreased	animal and human	protect	Inhibit L-type calcium channel-a1C expression	⁴⁴44 Guo L, Qiu Z, Wei L, Yu X, Gao X, Jiang S, et al. The microRNA-328 regulates hypoxic pulmonary hypertension by targeting at insulin growth factor 1 receptor and L-type calcium channel-a1C. Hypertension. 2012;59(5):1006-13.
miR-26a	decreased	animal and human	unknow	unknow	²⁸28 Schlosser K, White RJ, Stewart DJ. miR-26a linked to pulmonary hypertension by global assessment of circulating extracellular MicroRNAs. Am J Respir Crit Care Med. 2013;188(12):1472-5.
miR-424	decreased	animal	protect	FGF2 pathways	⁴²42 Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013;19(1):74-82.
miR-503	decreased	animal	protect	FGF2 pathways	⁴²42 Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013;19(1):74-82.

Authors’ roles & responsibilities
ZZ	Study conception and design
ZF	Study conception and design
XH	Analysis and/or interpretation of the data
SZ	Final approval of the manuscript

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[1] Correspondence address: Shenghua Zhou, The Second Xiangya Hospital, Central South University, Middle Ren-Min road, No.139 - Changsha, Huan Province, P.R. China, Zip code: 410011. E-mail: zhoushenghua2011@163.com