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 5

Assessment of LV morphology and function in a pig model of IR injury.

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Assessment of LV morphology and function in a pig model of IR injury. Ca...
Cardiac MRI recordings in the experimental groups at end-diastole (ED) and end-systole (ES). At day 28, the CHIR + FGF1-NP-treated group revealed significant reduction in infarct size compared with the untreated IR group (B). On the contrary, EF (C), CO (D), and SV (E) were significantly greater in CHIR + FGF1-NP–treated groups than in untreated IR groups while LV end-diastolic volume and LV end-systolic volume were significantly lower (F and G). Data are given as means ± SEM. There were 4 animals per group. Statistical analysis: 2-way ANOVA with Dunn’s multiple comparisons test. *P < 0.01 vs. pre-IR; †P < 0.05 vs. week 1; ‡P < 0.05 vs. IR. Macroscopic areas of infarction/fibrosis/scar (H) at after-IR day 28 in serial transverse sections of fresh (scale bar: 1 cm) representative micrographs of Sirius Red/Fast Green histochemical staining, revealing areas of infarcted (red, nonviable) and noninfarcted (green, viable) zones (I) (scale bar: 1 mm) and quantification of left anterior wall thickness (J). 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.