TY - JOUR
T1 - Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1
AU - Fan, Chengming
AU - Oduk, Yasin
AU - Zhao, Meng
AU - Lou, Xi
AU - Tang, Yawen
AU - Pretorius, Danielle
AU - Valarmathi, Mani T.
AU - Walcott, Gregory P.
AU - Yang, Jinfu
AU - Menasche, Philippe
AU - Krishnamurthy, Prasanna
AU - Zhu, Wuqiang
AU - Zhang, Jianyi
N1 - Funding Information:
We would also like to thank Mary Flowers Braswell for her donation of the “Echocardiographic Imaging System,” for research purposes. This work was supported by NIH grants (NHLBI R01 grants: HL095077, HL114120, HL131017, HL142627, and U01 HL134764) and by an American Heart Association-National Scientist Development grant (16SDG30410018).
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/6/18
Y1 - 2020/6/18
N2 - The mortality of patients suffering from acute myocardial infarction is linearly related to the infarct size. As regeneration of cardiomyocytes from cardiac progenitor cells is minimal in the mammalian adult heart, we have explored a new therapeutic approach, which leverages the capacity of nanomaterials to release chemicals over time to promote myocardial protection and infarct size reduction. Initial screening identified 2 chemicals, FGF1 and CHIR99021 (a Wnt1 agonist/GSK-3β antagonist), which synergistically enhance cardiomyocyte cell cycle in vitro. Poly-lactic-co-glycolic acid nanoparticles (NPs) formulated with CHIR99021 and FGF1 (CHIR + FGF1-NPs) provided an effective slow-release system for up to 4 weeks. Intramyocardial injection of CHIR + FGF1-NPs enabled myocardial protection via reducing infarct size by 20%–30% in mouse or pig models of postinfarction left ventricular (LV) remodeling. This LV structural improvement was accompanied by preservation of cardiac contractile function. Further investigation revealed that CHIR + FGF1-NPs resulted in a reduction of cardiomyocyte apoptosis and increase of angiogenesis. Thus, using a combination of chemicals and an NP-based prolonged-release system that works synergistically, this study demonstrates a potentially novel therapy for LV infarct size reduction in hearts with acute myocardial infarction.
AB - The mortality of patients suffering from acute myocardial infarction is linearly related to the infarct size. As regeneration of cardiomyocytes from cardiac progenitor cells is minimal in the mammalian adult heart, we have explored a new therapeutic approach, which leverages the capacity of nanomaterials to release chemicals over time to promote myocardial protection and infarct size reduction. Initial screening identified 2 chemicals, FGF1 and CHIR99021 (a Wnt1 agonist/GSK-3β antagonist), which synergistically enhance cardiomyocyte cell cycle in vitro. Poly-lactic-co-glycolic acid nanoparticles (NPs) formulated with CHIR99021 and FGF1 (CHIR + FGF1-NPs) provided an effective slow-release system for up to 4 weeks. Intramyocardial injection of CHIR + FGF1-NPs enabled myocardial protection via reducing infarct size by 20%–30% in mouse or pig models of postinfarction left ventricular (LV) remodeling. This LV structural improvement was accompanied by preservation of cardiac contractile function. Further investigation revealed that CHIR + FGF1-NPs resulted in a reduction of cardiomyocyte apoptosis and increase of angiogenesis. Thus, using a combination of chemicals and an NP-based prolonged-release system that works synergistically, this study demonstrates a potentially novel therapy for LV infarct size reduction in hearts with acute myocardial infarction.
UR - http://www.scopus.com/inward/record.url?scp=85086746641&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086746641&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.132796
DO - 10.1172/jci.insight.132796
M3 - Article
C2 - 32453715
AN - SCOPUS:85086746641
VL - 5
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 12
M1 - e132796
ER -