Editorial Circulating MicroRNAs Link Inflammation to Impaired Wound Healing in Diabetes Reinier A. Boon
S
oon after their discovery in 1993, it became clear that microRNAs (miRs) regulate virtually all cellular processes.1 Since then, many miRs have been described to coordinate gene expression programs in the context of cardiovascular disease, including diabetes mellitus.2,3 MiRs usually perform their duties intracellularly, but interest in extracellular miRs as biomarkers or intercellular messengers has risen recently.4,5 In the cardiovascular system, it has been shown that miRs can travel between endothelial cells, smooth muscle cells, cardiac fibroblasts, and cardiomyocytes, thereby affecting gene expression in recipient cells.6–8 Next to their role in intercellular communication, circulating miRs were also shown to be powerful biomarkers for various cardiovascular conditions.9–11 In this issue of ATVB, Dangwal et al12 show that miR-191 is both a circulating biomarker for type-2 diabetes mellitus and an intercellular messenger with a potent effect on wound healing.
See accompanying article on page 1480 Using miR microarrays, the authors were able to identify several miRs that are differentially detectable in the plasma of patients with type-2 diabetes mellitus compared with healthy controls.12 These miRs include miR-191 and miR200b. Interestingly, the reduction of miR-191 in plasma of patients with type-2 diabetes mellitus was also seen by Zampetaki et al.11 However, Dangwal et al12 also noticed that the presence of chronic wounds essentially reversed the extracellular levels of miR-191 in the circulation. Rather than dismissing this seemingly contradictory finding, the authors set out to investigate the meaning of this observation. What the groups of Tschoepe and Thum found is that inflammatory stimuli that are present in wound fluid induce the secretion of miR-191 by endothelial cells.12 This finding could explain the observation that miR-191 increases in type-2 diabetes mellitus patients with wound healing complications, compared with type-2 diabetes mellitus patients without wounds. The authors then went on and tested whether miR191 may have a functional effect in endothelial cells and dermal fibroblasts that would potentially show a role of miR-191 in wound healing in diabetic conditions. Indeed, this was the case because the authors showed that secreted miR-191 can
be taken up by other endothelial cells and dermal fibroblasts. In recipient cells, miR-191 impaired angiogenesis, migration, and apoptosis by targeting the tight junction protein ZO-1 (Figure 1). Because ZO-1 has been shown to be essential for migration,13 miR-191-mediated downregulation could very well explain the migration and angiogenesis defects observed after overexpression of miR-191. As all miRs are capable of targeting multiple target mRNAs, it is likely that other factors contribute to the effects of miR-191. Evidence that this is indeed the case comes from the observation that miR-191 has effects beyond regulation of migration, namely apoptosis induction. Which target mRNAs are involved in this remains to be seen, but it is clear that the effects of miR-191 on apoptosis are cell context–dependent because miR-191 was shown to inhibit apoptosis in hepatocellular carcinoma.14 Although these findings provide evidence for functional transfer of miR-191 from endothelial cells to other endothelial cells and fibroblasts, the study also highlights a limitation of the use of miR-191 as biomarker for type-2 diabetes mellitus. Even though miR-191 is reproducibly reduced in plasma of type-2 diabetes mellitus patients,11,12 patients with wound healing problems have the same plasma miR-191 levels as healthy controls. Finally, the study by Dangwal et al12 shows another interesting example of how miRs travel from one cell to another to crucially affect the gene expression pattern and phenotype of the recipient cells with potent effects on wound healing. These types of cell–cell communication are now becoming widely established in the field, and in the Diabetes: Chronic wound
Normal wound healing Wound
Inflammation
EC
miR-191 Angiogenesis
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.115.305670
Angiogenesis
FB
Migration
From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Frankfurt University, Frankfurt, Germany. Correspondence to Reinier A. Boon, Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2015;35:1296-1297. DOI: 10.1161/ATVBAHA.115.305670.) © 2015 American Heart Association, Inc.
miR-191
Migration
Wound healing
Figure. The left side depicts normal wound healing, with endothelial cells (EC) and fibroblasts (FB) contributing to wound healing. In type-2 diabetes mellitus patients with chronic wounds (right), inflammation increases miR-191 levels in endothelial cells. MiR-191 is secreted by endothelial cells and taken up by endothelial cells and fibroblasts to inhibit angiogenesis and migration, thereby inhibiting wound healing.
Downloaded from http://atvb.ahajournals.org/ by guest on June 2, 2015 1296
Boon miR-191 in Diabetes and Wound Healing 1297 future, even more diverse forms of cell–cell communication in the cardiovascular and other systems will undoubtedly be discovered. Furthermore, the study also opens up possibilities to potentially treat chronic wounds in diabetes mellitus patients. As the skin is an easily accessible organ and the potency of anti-miRs has been proven extensively, even in clinical trials,15 inhibition of miR-191 promises to be a feasible strategy to enhance wound healing in patients with diabetes mellitus.
Sources of Funding The author is supported by the Deutsche Forschungsgemeinschaft (SFB834/B9).
Disclosures None.
References 1. Ambros V. microRNAs: tiny regulators with great potential. Cell. 2001;107:823–826. 2. Beltrami C, Angelini TG, Emanueli C. Noncoding RNAs in diabetes vascular complications. J Mol Cell Cardiol. 2014. pii: S0022-2828(14)00426-X. doi: 10.1016/j.yjmcc.2014.12.014. [Epub ahead of print]. 3. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469:336–342. doi: 10.1038/nature09783. 4. Boon RA, Vickers KC. Intercellular transport of microRNAs. Arterioscler Thromb Vasc Biol. 2013;33:186–192. doi: 10.1161/ ATVBAHA.112.300139. 5. Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Röxe T, Müller-Ardogan M, Bonauer A, Zeiher AM, Dimmeler S. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010;107:677–684. doi: 10.1161/CIRCRESAHA.109.215566. 6. Hergenreider E, Heydt S, Tréguer K, Boettger T, Horrevoets AJ, Zeiher AM, Scheffer MP, Frangakis AS, Yin X, Mayr M, Braun T, Urbich C, Boon RA, Dimmeler S. Atheroprotective communication between
endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol. 2012;14:249–256. doi: 10.1038/ncb2441. 7. Bang C, Batkai S, Dangwal S, et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest. 2014;124:2136–2146. doi: 10.1172/JCI70577. 8. Loyer X, Vion AC, Tedgui A, Boulanger CM. Microvesicles as cell–cell messengers in cardiovascular diseases. Circ Res. 2014;114:345–353. doi: 10.1161/CIRCRESAHA.113.300858. 9. Fichtlscherer S, Zeiher AM, Dimmeler S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol. 2011;31:2383–2390. doi: 10.1161/ATVBAHA.111.226696. 10. Guay C, Regazzi R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol. 2013;9:513–521. doi: 10.1038/nrendo.2013.86. 11. Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, Shah A, Willeit J, Mayr M. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107:810–817. doi: 10.1161/ CIRCRESAHA.110.226357. 12. Dangwal S, Stratmann B, Bang C, Lorenzen JM, Kumarswamy R, Fiedler J, Falk CS, Scholz CJ, Thum T, Tschoepe D. Impairment of wound healing in patients with type 2 diabetes mellitus influences circulating microRNA patterns via inflammatory cytokines. Arterioscler Thromb Vasc Biol. 2015;35:1480–1488. doi: 10.1161/ATVBAHA.114.305048. 13. Huo L, Wen W, Wang R, Kam C, Xia J, Feng W, Zhang M. Cdc42-dependent formation of the ZO-1/MRCKβ complex at the leading edge controls cell migration. EMBO J. 2011;30:665–678. doi: 10.1038/emboj.2010.353. 14. Elyakim E, Sitbon E, Faerman A, Tabak S, Montia E, Belanis L, Dov A, Marcusson EG, Bennett CF, Chajut A, Cohen D, Yerushalmi N. hsamiR-191 is a candidate oncogene target for hepatocellular carcinoma therapy. Cancer Res. 2010;70:8077–8087. doi: 10.1158/0008-5472. CAN-10-1313. 15. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368:1685–1694. doi: 10.1056/ NEJMoa1209026.
Key Words: diabetes mellitus ◼ microRNA ◼ wound healing
Downloaded from http://atvb.ahajournals.org/ by guest on June 2, 2015
Circulating MicroRNAs Link Inflammation to Impaired Wound Healing in Diabetes Reinier A. Boon Arterioscler Thromb Vasc Biol. 2015;35:1296-1297 doi: 10.1161/ATVBAHA.115.305670 Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 1079-5642. Online ISSN: 1524-4636
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://atvb.ahajournals.org/content/35/6/1296
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular Biology is online at: http://atvb.ahajournals.org//subscriptions/
Downloaded from http://atvb.ahajournals.org/ by guest on June 2, 2015
S
oon after their discovery in 1993, it became clear that microRNAs (miRs) regulate virtually all cellular processes.1 Since then, many miRs have been described to coordinate gene expression programs in the context of cardiovascular disease, including diabetes mellitus.2,3 MiRs usually perform their duties intracellularly, but interest in extracellular miRs as biomarkers or intercellular messengers has risen recently.4,5 In the cardiovascular system, it has been shown that miRs can travel between endothelial cells, smooth muscle cells, cardiac fibroblasts, and cardiomyocytes, thereby affecting gene expression in recipient cells.6–8 Next to their role in intercellular communication, circulating miRs were also shown to be powerful biomarkers for various cardiovascular conditions.9–11 In this issue of ATVB, Dangwal et al12 show that miR-191 is both a circulating biomarker for type-2 diabetes mellitus and an intercellular messenger with a potent effect on wound healing.
See accompanying article on page 1480 Using miR microarrays, the authors were able to identify several miRs that are differentially detectable in the plasma of patients with type-2 diabetes mellitus compared with healthy controls.12 These miRs include miR-191 and miR200b. Interestingly, the reduction of miR-191 in plasma of patients with type-2 diabetes mellitus was also seen by Zampetaki et al.11 However, Dangwal et al12 also noticed that the presence of chronic wounds essentially reversed the extracellular levels of miR-191 in the circulation. Rather than dismissing this seemingly contradictory finding, the authors set out to investigate the meaning of this observation. What the groups of Tschoepe and Thum found is that inflammatory stimuli that are present in wound fluid induce the secretion of miR-191 by endothelial cells.12 This finding could explain the observation that miR-191 increases in type-2 diabetes mellitus patients with wound healing complications, compared with type-2 diabetes mellitus patients without wounds. The authors then went on and tested whether miR191 may have a functional effect in endothelial cells and dermal fibroblasts that would potentially show a role of miR-191 in wound healing in diabetic conditions. Indeed, this was the case because the authors showed that secreted miR-191 can
be taken up by other endothelial cells and dermal fibroblasts. In recipient cells, miR-191 impaired angiogenesis, migration, and apoptosis by targeting the tight junction protein ZO-1 (Figure 1). Because ZO-1 has been shown to be essential for migration,13 miR-191-mediated downregulation could very well explain the migration and angiogenesis defects observed after overexpression of miR-191. As all miRs are capable of targeting multiple target mRNAs, it is likely that other factors contribute to the effects of miR-191. Evidence that this is indeed the case comes from the observation that miR-191 has effects beyond regulation of migration, namely apoptosis induction. Which target mRNAs are involved in this remains to be seen, but it is clear that the effects of miR-191 on apoptosis are cell context–dependent because miR-191 was shown to inhibit apoptosis in hepatocellular carcinoma.14 Although these findings provide evidence for functional transfer of miR-191 from endothelial cells to other endothelial cells and fibroblasts, the study also highlights a limitation of the use of miR-191 as biomarker for type-2 diabetes mellitus. Even though miR-191 is reproducibly reduced in plasma of type-2 diabetes mellitus patients,11,12 patients with wound healing problems have the same plasma miR-191 levels as healthy controls. Finally, the study by Dangwal et al12 shows another interesting example of how miRs travel from one cell to another to crucially affect the gene expression pattern and phenotype of the recipient cells with potent effects on wound healing. These types of cell–cell communication are now becoming widely established in the field, and in the Diabetes: Chronic wound
Normal wound healing Wound
Inflammation
EC
miR-191 Angiogenesis
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.115.305670
Angiogenesis
FB
Migration
From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Frankfurt University, Frankfurt, Germany. Correspondence to Reinier A. Boon, Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2015;35:1296-1297. DOI: 10.1161/ATVBAHA.115.305670.) © 2015 American Heart Association, Inc.
miR-191
Migration
Wound healing
Figure. The left side depicts normal wound healing, with endothelial cells (EC) and fibroblasts (FB) contributing to wound healing. In type-2 diabetes mellitus patients with chronic wounds (right), inflammation increases miR-191 levels in endothelial cells. MiR-191 is secreted by endothelial cells and taken up by endothelial cells and fibroblasts to inhibit angiogenesis and migration, thereby inhibiting wound healing.
Downloaded from http://atvb.ahajournals.org/ by guest on June 2, 2015 1296
Boon miR-191 in Diabetes and Wound Healing 1297 future, even more diverse forms of cell–cell communication in the cardiovascular and other systems will undoubtedly be discovered. Furthermore, the study also opens up possibilities to potentially treat chronic wounds in diabetes mellitus patients. As the skin is an easily accessible organ and the potency of anti-miRs has been proven extensively, even in clinical trials,15 inhibition of miR-191 promises to be a feasible strategy to enhance wound healing in patients with diabetes mellitus.
Sources of Funding The author is supported by the Deutsche Forschungsgemeinschaft (SFB834/B9).
Disclosures None.
References 1. Ambros V. microRNAs: tiny regulators with great potential. Cell. 2001;107:823–826. 2. Beltrami C, Angelini TG, Emanueli C. Noncoding RNAs in diabetes vascular complications. J Mol Cell Cardiol. 2014. pii: S0022-2828(14)00426-X. doi: 10.1016/j.yjmcc.2014.12.014. [Epub ahead of print]. 3. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469:336–342. doi: 10.1038/nature09783. 4. Boon RA, Vickers KC. Intercellular transport of microRNAs. Arterioscler Thromb Vasc Biol. 2013;33:186–192. doi: 10.1161/ ATVBAHA.112.300139. 5. Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Röxe T, Müller-Ardogan M, Bonauer A, Zeiher AM, Dimmeler S. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010;107:677–684. doi: 10.1161/CIRCRESAHA.109.215566. 6. Hergenreider E, Heydt S, Tréguer K, Boettger T, Horrevoets AJ, Zeiher AM, Scheffer MP, Frangakis AS, Yin X, Mayr M, Braun T, Urbich C, Boon RA, Dimmeler S. Atheroprotective communication between
endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol. 2012;14:249–256. doi: 10.1038/ncb2441. 7. Bang C, Batkai S, Dangwal S, et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest. 2014;124:2136–2146. doi: 10.1172/JCI70577. 8. Loyer X, Vion AC, Tedgui A, Boulanger CM. Microvesicles as cell–cell messengers in cardiovascular diseases. Circ Res. 2014;114:345–353. doi: 10.1161/CIRCRESAHA.113.300858. 9. Fichtlscherer S, Zeiher AM, Dimmeler S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol. 2011;31:2383–2390. doi: 10.1161/ATVBAHA.111.226696. 10. Guay C, Regazzi R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol. 2013;9:513–521. doi: 10.1038/nrendo.2013.86. 11. Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, Shah A, Willeit J, Mayr M. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107:810–817. doi: 10.1161/ CIRCRESAHA.110.226357. 12. Dangwal S, Stratmann B, Bang C, Lorenzen JM, Kumarswamy R, Fiedler J, Falk CS, Scholz CJ, Thum T, Tschoepe D. Impairment of wound healing in patients with type 2 diabetes mellitus influences circulating microRNA patterns via inflammatory cytokines. Arterioscler Thromb Vasc Biol. 2015;35:1480–1488. doi: 10.1161/ATVBAHA.114.305048. 13. Huo L, Wen W, Wang R, Kam C, Xia J, Feng W, Zhang M. Cdc42-dependent formation of the ZO-1/MRCKβ complex at the leading edge controls cell migration. EMBO J. 2011;30:665–678. doi: 10.1038/emboj.2010.353. 14. Elyakim E, Sitbon E, Faerman A, Tabak S, Montia E, Belanis L, Dov A, Marcusson EG, Bennett CF, Chajut A, Cohen D, Yerushalmi N. hsamiR-191 is a candidate oncogene target for hepatocellular carcinoma therapy. Cancer Res. 2010;70:8077–8087. doi: 10.1158/0008-5472. CAN-10-1313. 15. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368:1685–1694. doi: 10.1056/ NEJMoa1209026.
Key Words: diabetes mellitus ◼ microRNA ◼ wound healing
Downloaded from http://atvb.ahajournals.org/ by guest on June 2, 2015
Circulating MicroRNAs Link Inflammation to Impaired Wound Healing in Diabetes Reinier A. Boon Arterioscler Thromb Vasc Biol. 2015;35:1296-1297 doi: 10.1161/ATVBAHA.115.305670 Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 1079-5642. Online ISSN: 1524-4636
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://atvb.ahajournals.org/content/35/6/1296
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular Biology is online at: http://atvb.ahajournals.org//subscriptions/
Downloaded from http://atvb.ahajournals.org/ by guest on June 2, 2015
