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 6

Morphometric analysis of LV hypertrophy, cardiomyocyte cell cycle, and apoptosis in a pig model of IR injury.

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Morphometric analysis of LV hypertrophy, cardiomyocyte cell cycle, and a...
(A) Expression of a cardiac contractile protein, α-sarcomeric actinin (red, α-SA), and a plasma membrane marker, wheat germ agglutinin (green, WGA), in the periinfarct border zone sections 28 days after MI (scale bar: 50 μm). (B and C) Markers of cardiomyocyte and LV hypertrophy showing a reduction in the treated group. (D–G) Cardiomyocyte cell cycle activity assessed by dual stainings for Ki-67 and cTnT (D and F) and for PH3 and cTnT (E and G). Data are given as means ± SEM. There were 4 animals per group. (H–K) Apoptosis in the infarct, border, and remote zones (IZ, BZ, and RZ, respectively), assessed by staining for TUNEL (red) and the pig cardiac-specific contractile protein (green, α-SA) (scale bar: 50 μm). The number of apoptotic cells did not differ between the control and treated groups in the RZ (K) but was significantly reduced in the treatment group in the IZ and BZ (I and J). Data are given as means ± SEM. There were 4 animals per group. Statistical analysis: 1-way ANOVA with Dunn’s multiple comparisons test (B, C, and I–K) and t test (F and G). *P < 0.05 vs. control; †P < 0.05 vs. IR (B and C); *P < 0.01 vs. control; †P < 0.05 vs. IR (I–K).