TY - JOUR
T1 - A small molecule HIF-1α stabilizer that accelerates diabetic wound healing
AU - Li, Guodong
AU - Ko, Chung Nga
AU - Li, Dan
AU - Yang, Chao
AU - Wang, Wanhe
AU - Yang, Guan Jun
AU - Di Primo, Carmelo
AU - Wong, Vincent Kam Wai
AU - Xiang, Yaozu
AU - Lin, Ligen
AU - Ma, Dik Lung
AU - Leung, Chung Hang
N1 - Funding Information:
We would like to thank Prof. Simon Ming-Yuen Lee, Dr. Rui-Bing Wang, Dr. Hiu-Yee Kwan, Dr. Li Wang and Mr. Rui-Hong Chen for technical assistance. We also acknowledged the animal facility of the Faculty of Health Sciences, University of Macau. This work is supported by the Health and Medical Research Fund (HMRF/ 14150561), the National Natural Science Foundation of China (22077109, 21775131 and 81872754), the Hong Kong Baptist University Century Club Sponsorship Scheme 2020, the Interdisciplinary Research Matching Scheme (RC-IRMS/16-17/03), the Interdisciplinary Research Clusters Matching Scheme (RC-IRCs/17-18/03), SKLEBA and HKBU Strategic Development Fund (SKLP_1920_P02), the Science and Technology Development Fund, Macao SAR (0072/2018/A2 and 0031/2019/A1), the University of Macau (MYRG2019-00002-ICMS, MYRG2018-00037-ICMS and MYRG2018-00187-ICMS).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6/7
Y1 - 2021/6/7
N2 - Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.
AB - Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.
UR - http://www.scopus.com/inward/record.url?scp=85107560063&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-23448-7
DO - 10.1038/s41467-021-23448-7
M3 - Journal article
C2 - 34099651
AN - SCOPUS:85107560063
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3363
ER -
