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. 2006 Oct 17;103(42):15546-51.
doi: 10.1073/pnas.0607382103. Epub 2006 Oct 10.

FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction

Felix B Engel  1 , Patrick C H Hsieh, Richard T Lee, Mark T Keating
Affiliations

FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction

Felix B Engel et al. Proc Natl Acad Sci U S A. .

Abstract

Mammalian cardiomyocytes have limited proliferation potential, and acutely injured mammalian hearts do not regenerate adequately. Instead, injured myocardium develops fibrosis and scarring. Here we show that FGF1/p38 MAP kinase inhibitor treatment after acute myocardial injury in 8- to 10-week-old rats increases cardiomyocyte mitosis. At 3 months after injury, 4 weeks of FGF1/p38 MAP kinase inhibitor therapy results in reduced scarring and wall thinning, with markedly improved cardiac function. In contrast, p38 MAP kinase inhibition alone fails to rescue heart function despite increased cardiomyocyte mitosis. FGF1 improves angiogenesis, possibly contributing to the survival of newly generated cardiomyocytes. Our data indicate that FGF1 and p38 MAP kinase, proteins involved in cardiomyocyte proliferation and angiogenesis during development, may be delivered therapeutically to enhance cardiac regeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
FGF1/p38 inhibitor treatment induces cardiomyocyte mitosis in vivo. Rats were treated after myocardial infarction (MI) with saline plus BSA (control), SB203580 plus BSA (p38i), saline plus FGF1 (FGF1), or SB203580 plus FGF1 (FGF1/p38i). Two weeks after treatment, heart sections were analyzed for cell cycle activation (Cylin D2, Cyclin A) and mitosis (H3P) of cardiomyocytes within the scar area and the infarct border zone. (A) FGF1 and/or p38i significantly increased the number of Cyclin D2-positive cardiomyocytes. (B) Examples of heart section from sham or FGF1/p38i-treated animals stained for Caveolin 3 (green) and Cyclin D2 (red). (C) FGF1 and/or p38i significantly increased the number of Cyclin A-positive cardiomyocytes. (D) FGF1 and/or p38i significantly increased the number of H3P-positive cardiomyocytes. (E) Six examples of heart section after FGF1/p38i treatment stained for Caveolin 3 (green) and H3P (red). Data are ±SEM; n ≥ 9 in each group; NS, not significant; ∗∗, P < 0.01.
Fig. 2.
Fig. 2.
FGF1/p38 inhibitor treatment improves heart function. Rats were treated after myocardial infarction (MI) with saline plus BSA (control), SB203580 plus BSA (p38i), saline plus FGF1 (FGF1), or SB203580 plus FGF1 (FGF1/p38i). Hearts were analyzed by using echocardiography and trichrome stain of transverse heart sections. (A and B) FGF1 and/or p38i significantly improved left ventricular %FS 1 and 14 days after MI. %FS was calculated as (EDD − ESD)/EDD × 100%, where EDD is end-diastolic dimension and ESD is end-systolic dimension. (C) FGF1 and/or p38i significantly decreased left ventricular scarring. Percentage of scar volume was determined as fibrotic area/(fibrotic + nonfibrotic area) using seven sections from apex to base, 1.2 mm apart. (D) FGF1 and/or p38i significantly decreased ventricular wall thinning. The thinning index is the ratio of minimal infarct wall thickness and maximal septal wall thickness using sections 1–4 from base. (E) FGF1 and/or p38i significantly decreased left ventricular muscle loss. Percentage of left ventricular muscle loss was determined as circumference of the left ventricular wall containing at least 75% scar area/circumference of the left ventricular wall based on all sections. (F) Examples of heart sections stained for scar tissue (blue) and muscle tissue (brown) from base to apex in an interval of 2.4 mm 2 weeks after treatment. Data are ±SEM; n ≥ 9 in each group; NS, not significant; ∗, P < 0.05; ∗∗, P < 0.01.
Fig. 3.
Fig. 3.
FGF1/p38 inhibitor improved heart function 3 months after myocardial infarction. Rats were treated after myocardial infarction (MI) with saline plus BSA (control), SB203580 plus BSA (p38i), saline plus FGF1 (FGF1), or SB203580 plus FGF1 (FGF1/p38i). Hearts were analyzed by using echocardiography and trichrome stain of transverse heart sections 3 months after treatment. Note that treatment was stopped after 1 month. (A and B) FGF1/p38i and FGF1 significantly improved %FS 1 day and 3 months after MI. In contrast, %FS after p38i treatment was only improved at day 1. (C) FGF1 and/or p38i significantly decreased scar formation. The percentage of scar volume was determined as fibrotic area/(fibrotic + nonfibrotic area) using nine sections from apex to base, 1.3 mm apart. (D) FGF1/p38i and FGF1 significantly decreased ventricular wall thinning but not p38i. The thinning index was determined by using sections 1–6 from base. (E) FGF1/p38i and FGF1 significantly decreased left ventricular muscle loss but not p38i. The percentage of left ventricular muscle loss was determined as circumference of the left ventricular wall containing at least 75% scar area/circumference of the left ventricular wall based on all sections. (F) Examples of heart sections stained for scar tissue (blue) and muscle tissue (brown) from base to apex in an interval of 2.6 mm 3 months after treatment. Data are ±SEM; n ≥ 9 in each group; NS, not significant; ∗, P < 0.05; ∗∗, P < 0.01.
Fig. 4.
Fig. 4.
FGF1/p38 inhibitor treatment increases angiogenesis. (A) FGF1/p38i and FGF1, but not p38i, significantly increased angiogenesis of the scar area at 3 months. (B) Examples of vessel staining 3 months after MI using vessel markers smooth muscle actin (SMA, smooth muscle cells, fluorescent green) and von Willebrand factor (vWF, endothelial cells, red) and cardiomyocyte-specific marker Caveolin 3 (pale green). (C) Examples of vessel staining of heart sections from rats 3 months after coronary ligation treated with FGF1/p38i. Data are ±SEM; n ≥ 7 in each group; NS, not significant; ∗, P < 0.05; ∗∗, P < 0.01.
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