Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2

Xiaowei Zhang, Xiaohong Wang, Hongyan Zhu, Evangelia G. Kranias, Yao Liang Tang, Tianqing Peng, Jiang Chang, Guo Chang Fan

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Heat shock proteins (Hsps) are well appreciated as intrinsic protectors of cardiomyocytes against numerous stresses. Recent studies have indicated that Hsp20 (HspB6), a small heat shock protein, was increased in blood from cardiomyopathic hamsters. However, the exact source of the increased circulating Hsp20 and its potential role remain obscure. In this study, we observed that the circulating Hsp20 was increased in a transgenic mouse model with cardiac-specific overexpression of Hsp20, compared with wild-type mice, suggesting its origin from cardiomyocytes. Consistently, culture media harvested from Hsp20-overexpressing cardiomyocytes by Ad.Hsp20 infection contained an increased amount of Hsp20, compared to control media. Furthermore, we identified that Hsp20 was secreted through exosomes, independent of the endoplasmic reticulum-Golgi pathway. To investigate whether extracellular Hsp20 promotes angiogenesis, we treated human umbilical vein endothelial cells (HUVECs) with recombinant human Hsp20 protein, and observed that Hsp20 dose-dependently promoted HUVEC proliferation, migration and tube formation. Moreover, a protein binding assay and immunostaining revealed an interaction between Hsp20 and VEGFR2. Accordingly, stimulatory effects of Hsp20 on HUVECs were blocked by a VEGFR2 neutralizing antibody and CBO-P11 (a VEGFR inhibitor). These in vitro data are consistent with the in vivo findings that capillary density was significantly enhanced in Hsp20-overexpressing hearts, compared to non-transgenic hearts. Collectively, our findings demonstrate that Hsp20 serves as a novel cardiokine in regulating myocardial angiogenesis through activation of the VEGFR signaling cascade.

Original languageEnglish (US)
Article numbere32765
JournalPloS one
Volume7
Issue number3
DOIs
StatePublished - Mar 12 2012

Fingerprint

Endothelial cells
Human Umbilical Vein Endothelial Cells
angiogenesis
Cardiac Myocytes
Chemical activation
heat shock proteins
heart
exosomes
Small Heat-Shock Proteins
Exosomes
protein binding
Cell proliferation
Heat-Shock Proteins
Neutralizing Antibodies
neutralizing antibodies
hamsters
Protein Binding
Cricetinae
Endoplasmic Reticulum
endoplasmic reticulum

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. / Zhang, Xiaowei; Wang, Xiaohong; Zhu, Hongyan; Kranias, Evangelia G.; Tang, Yao Liang; Peng, Tianqing; Chang, Jiang; Fan, Guo Chang.

In: PloS one, Vol. 7, No. 3, e32765, 12.03.2012.

Research output: Contribution to journalArticle

Zhang, X, Wang, X, Zhu, H, Kranias, EG, Tang, YL, Peng, T, Chang, J & Fan, GC 2012, 'Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2', PloS one, vol. 7, no. 3, e32765. https://doi.org/10.1371/journal.pone.0032765
Zhang, Xiaowei ; Wang, Xiaohong ; Zhu, Hongyan ; Kranias, Evangelia G. ; Tang, Yao Liang ; Peng, Tianqing ; Chang, Jiang ; Fan, Guo Chang. / Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. In: PloS one. 2012 ; Vol. 7, No. 3.
@article{75ccf205d759446b974fa1c1fa8097c4,
title = "Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2",
abstract = "Heat shock proteins (Hsps) are well appreciated as intrinsic protectors of cardiomyocytes against numerous stresses. Recent studies have indicated that Hsp20 (HspB6), a small heat shock protein, was increased in blood from cardiomyopathic hamsters. However, the exact source of the increased circulating Hsp20 and its potential role remain obscure. In this study, we observed that the circulating Hsp20 was increased in a transgenic mouse model with cardiac-specific overexpression of Hsp20, compared with wild-type mice, suggesting its origin from cardiomyocytes. Consistently, culture media harvested from Hsp20-overexpressing cardiomyocytes by Ad.Hsp20 infection contained an increased amount of Hsp20, compared to control media. Furthermore, we identified that Hsp20 was secreted through exosomes, independent of the endoplasmic reticulum-Golgi pathway. To investigate whether extracellular Hsp20 promotes angiogenesis, we treated human umbilical vein endothelial cells (HUVECs) with recombinant human Hsp20 protein, and observed that Hsp20 dose-dependently promoted HUVEC proliferation, migration and tube formation. Moreover, a protein binding assay and immunostaining revealed an interaction between Hsp20 and VEGFR2. Accordingly, stimulatory effects of Hsp20 on HUVECs were blocked by a VEGFR2 neutralizing antibody and CBO-P11 (a VEGFR inhibitor). These in vitro data are consistent with the in vivo findings that capillary density was significantly enhanced in Hsp20-overexpressing hearts, compared to non-transgenic hearts. Collectively, our findings demonstrate that Hsp20 serves as a novel cardiokine in regulating myocardial angiogenesis through activation of the VEGFR signaling cascade.",
author = "Xiaowei Zhang and Xiaohong Wang and Hongyan Zhu and Kranias, {Evangelia G.} and Tang, {Yao Liang} and Tianqing Peng and Jiang Chang and Fan, {Guo Chang}",
year = "2012",
month = "3",
day = "12",
doi = "10.1371/journal.pone.0032765",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2

AU - Zhang, Xiaowei

AU - Wang, Xiaohong

AU - Zhu, Hongyan

AU - Kranias, Evangelia G.

AU - Tang, Yao Liang

AU - Peng, Tianqing

AU - Chang, Jiang

AU - Fan, Guo Chang

PY - 2012/3/12

Y1 - 2012/3/12

N2 - Heat shock proteins (Hsps) are well appreciated as intrinsic protectors of cardiomyocytes against numerous stresses. Recent studies have indicated that Hsp20 (HspB6), a small heat shock protein, was increased in blood from cardiomyopathic hamsters. However, the exact source of the increased circulating Hsp20 and its potential role remain obscure. In this study, we observed that the circulating Hsp20 was increased in a transgenic mouse model with cardiac-specific overexpression of Hsp20, compared with wild-type mice, suggesting its origin from cardiomyocytes. Consistently, culture media harvested from Hsp20-overexpressing cardiomyocytes by Ad.Hsp20 infection contained an increased amount of Hsp20, compared to control media. Furthermore, we identified that Hsp20 was secreted through exosomes, independent of the endoplasmic reticulum-Golgi pathway. To investigate whether extracellular Hsp20 promotes angiogenesis, we treated human umbilical vein endothelial cells (HUVECs) with recombinant human Hsp20 protein, and observed that Hsp20 dose-dependently promoted HUVEC proliferation, migration and tube formation. Moreover, a protein binding assay and immunostaining revealed an interaction between Hsp20 and VEGFR2. Accordingly, stimulatory effects of Hsp20 on HUVECs were blocked by a VEGFR2 neutralizing antibody and CBO-P11 (a VEGFR inhibitor). These in vitro data are consistent with the in vivo findings that capillary density was significantly enhanced in Hsp20-overexpressing hearts, compared to non-transgenic hearts. Collectively, our findings demonstrate that Hsp20 serves as a novel cardiokine in regulating myocardial angiogenesis through activation of the VEGFR signaling cascade.

AB - Heat shock proteins (Hsps) are well appreciated as intrinsic protectors of cardiomyocytes against numerous stresses. Recent studies have indicated that Hsp20 (HspB6), a small heat shock protein, was increased in blood from cardiomyopathic hamsters. However, the exact source of the increased circulating Hsp20 and its potential role remain obscure. In this study, we observed that the circulating Hsp20 was increased in a transgenic mouse model with cardiac-specific overexpression of Hsp20, compared with wild-type mice, suggesting its origin from cardiomyocytes. Consistently, culture media harvested from Hsp20-overexpressing cardiomyocytes by Ad.Hsp20 infection contained an increased amount of Hsp20, compared to control media. Furthermore, we identified that Hsp20 was secreted through exosomes, independent of the endoplasmic reticulum-Golgi pathway. To investigate whether extracellular Hsp20 promotes angiogenesis, we treated human umbilical vein endothelial cells (HUVECs) with recombinant human Hsp20 protein, and observed that Hsp20 dose-dependently promoted HUVEC proliferation, migration and tube formation. Moreover, a protein binding assay and immunostaining revealed an interaction between Hsp20 and VEGFR2. Accordingly, stimulatory effects of Hsp20 on HUVECs were blocked by a VEGFR2 neutralizing antibody and CBO-P11 (a VEGFR inhibitor). These in vitro data are consistent with the in vivo findings that capillary density was significantly enhanced in Hsp20-overexpressing hearts, compared to non-transgenic hearts. Collectively, our findings demonstrate that Hsp20 serves as a novel cardiokine in regulating myocardial angiogenesis through activation of the VEGFR signaling cascade.

UR - http://www.scopus.com/inward/record.url?scp=84863231848&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863231848&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0032765

DO - 10.1371/journal.pone.0032765

M3 - Article

C2 - 22427880

AN - SCOPUS:84863231848

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e32765

ER -