Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1
Chengming Fan, Yasin Oduk, Meng Zhao, Xi Lou, Yawen Tang, Danielle Pretorius, Mani T. Valarmathi, Gregory P. Walcott, Jinfu Yang, Philippe Menasche, Prasanna Krishnamurthy, Wuqiang Zhu, Jianyi Zhang
Chengming Fan, Yasin Oduk, Meng Zhao, Xi Lou, Yawen Tang, Danielle Pretorius, Mani T. Valarmathi, Gregory P. Walcott, Jinfu Yang, Philippe Menasche, Prasanna Krishnamurthy, Wuqiang Zhu, Jianyi Zhang
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Research Article Cardiology Therapeutics

Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1

Abstract

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.

Authors

Chengming Fan, Yasin Oduk, Meng Zhao, Xi Lou, Yawen Tang, Danielle Pretorius, Mani T. Valarmathi, Gregory P. Walcott, Jinfu Yang, Philippe Menasche, Prasanna Krishnamurthy, Wuqiang Zhu, Jianyi Zhang

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Figure 7

Evaluation of NP-mediated neo-angiogenesis in the pig model of IR injury.

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Evaluation of NP-mediated neo-angiogenesis in the pig model of IR injury...
(A) Expression of cardiac-specific regulatory protein (white, cTnT), smooth muscle protein (green, SM22α), and endothelium-specific lectin (red, IB4) in the infarct, border, and remote zones (IZ, BZ, and RZ, respectively) 28 days after MI (scale bar: 20 μm). (B–G) Vasculogenic responses showing that the 2-factor–loaded nanomaterials increased angiogenesis compared with IR-untreated hearts in the infarct (B and C) and border (D and E) zones but not in the remote one (F and G). Data are given as means ± SEM. There were 4 animals per group. (H–J) Proliferation of cardiac microvascular endothelial cells assessed by dual staining for IB4+ cells and both Ki-67 (H and I) and PH3 (H and J) (scale bar: 50 μm). The results suggest that CHIR + FGF1-NPs synergistically promoted pig cardiac microvascular endothelial cell cycle activation and progression. Data are given as means ± SEM. There were 4 animals per group. Statistical analysis: 1-way ANOVA with Dunn’s multiple comparisons test. *P < 0.01 vs. control; †P < 0.05 vs. IR (B–G); *P < 0.05 vs. control; †P < 0.01 vs. IR (I and J).