TY - JOUR
T1 - The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury
AU - Liao, Siyun
AU - Bodmer, Janet R.
AU - Azhar, Mohamad
AU - Newman, Gilbert
AU - Coffin, J. Douglas
AU - Doetschman, Thomas
AU - Schultz, Jo El J.
N1 - Funding Information:
This work was supported by grants from the American Heart Association ( SDG 23004N ), the Pharmaceutical Research and Manufacturers of America (Research Starter Grant), NIH/NHLBI R01 ( HL075633 ) to Jo El J. Schultz and ( HL070174 ) to Doetschman. The authors are grateful to Dr. Ming Zhou for his contribution of generating the initial construct for the FGF2 HMWKO mouse model. The authors would like to acknowledge M. Bender, A. Whitaker and S. Pawlowski for their excellent animal husbandry. Also, the authors would like to acknowledge Pfizer, Inc. (Groton, CT) for the generous gift of the FGFR inhibitor, PD173074.
PY - 2010/6
Y1 - 2010/6
N2 - Fibroblast growth factor 2 (FGF2) consists of multiple protein isoforms (low [LMW] and high molecular weight [HMW]), which are localized to different cellular compartments, indicating unique biological activity. We previously showed that the LMW isoform is important in protecting the heart from myocardial dysfunction associated with ischemia-reperfusion (I/R) injury, but the roles of the HMW isoforms remain unknown. To elucidate the role of HMW isoforms in I/R and cardioprotection, hearts from novel mouse models, in which the murine FGF2 HMWs are knocked out (HMWKO) or the human FGF2 24kDa HMW isoform is overexpressed (HMW Tg) and their wildtype (Wt) or non-transgenic (NTg) cohorts were subjected to an ex vivo work-performing heart model of I/R. There was a significant improvement in post-ischemic recovery of cardiac function in HMWKO hearts (76 ± 5%, p<0.05) compared to Wt hearts (55 ± 5%), with a corresponding decrease in HMW Tg function (line 20: 38 ± 6% and line 28: 33 ± 4%, p<0.05) compared to non-transgenic hearts (68 ± 9%). FGF2 LMW isoform was secreted from Wt and HMWKO hearts during I/R, and a FGF receptor (FGFR) inhibitor, PD173074 caused a decrease in cardiac function when administered in I/R in Wt and FGF2 HMWKO hearts (p<0.05), indicating that FGFR is involved in FGF2 LMW isoform's biological effect in ischemia-reperfusion injury. Moreover, overexpression of HMW isoform reduced FGFR1 phosphorylation/activation with no further decrease in the phosphorylation state in the presence of the FGFR inhibitor. Overall, our data indicate that HMW isoforms have a detrimental role in the development of post-ischemic myocardial dysfunction.
AB - Fibroblast growth factor 2 (FGF2) consists of multiple protein isoforms (low [LMW] and high molecular weight [HMW]), which are localized to different cellular compartments, indicating unique biological activity. We previously showed that the LMW isoform is important in protecting the heart from myocardial dysfunction associated with ischemia-reperfusion (I/R) injury, but the roles of the HMW isoforms remain unknown. To elucidate the role of HMW isoforms in I/R and cardioprotection, hearts from novel mouse models, in which the murine FGF2 HMWs are knocked out (HMWKO) or the human FGF2 24kDa HMW isoform is overexpressed (HMW Tg) and their wildtype (Wt) or non-transgenic (NTg) cohorts were subjected to an ex vivo work-performing heart model of I/R. There was a significant improvement in post-ischemic recovery of cardiac function in HMWKO hearts (76 ± 5%, p<0.05) compared to Wt hearts (55 ± 5%), with a corresponding decrease in HMW Tg function (line 20: 38 ± 6% and line 28: 33 ± 4%, p<0.05) compared to non-transgenic hearts (68 ± 9%). FGF2 LMW isoform was secreted from Wt and HMWKO hearts during I/R, and a FGF receptor (FGFR) inhibitor, PD173074 caused a decrease in cardiac function when administered in I/R in Wt and FGF2 HMWKO hearts (p<0.05), indicating that FGFR is involved in FGF2 LMW isoform's biological effect in ischemia-reperfusion injury. Moreover, overexpression of HMW isoform reduced FGFR1 phosphorylation/activation with no further decrease in the phosphorylation state in the presence of the FGFR inhibitor. Overall, our data indicate that HMW isoforms have a detrimental role in the development of post-ischemic myocardial dysfunction.
KW - Cardioprotection
KW - Fibroblast growth factor
KW - Fibroblast growth factor receptor
KW - Human or mouse FGF
KW - Ischemia-reperfusion injury
KW - Low or high molecular weight isoforms
UR - http://www.scopus.com/inward/record.url?scp=77952675539&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952675539&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2010.01.014
DO - 10.1016/j.yjmcc.2010.01.014
M3 - Article
C2 - 20116383
AN - SCOPUS:77952675539
SN - 0022-2828
VL - 48
SP - 1245
EP - 1254
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 6
ER -