Aging-Related Defects Are Associated With Adverse Cardiac Remodeling in a Mouse Model of Reperfused Myocardial Infarction
Marcin Bujak, MD,
Hyuk Jung Kweon, MD,
Khaled Chatila, MD,
Na Li, PhD,
George Taffet, MD and
Nikolaos G. Frangogiannis, MD, FACC*
Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, Texas.
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Figure 1 Senescent Animals Exhibited Impaired Phagocytosis of Dead Cardiomyocytes and Decreased Peak Neutrophil Infiltration in the Infarcted Myocardium
(A) After 72 h of reperfusion, young mice showed almost complete replacement of dead cardiomyocytes with granulation tissue (arrows). (B) In contrast, at the same timepoint senescent mouse infarcts exhibited delayed granulation tissue formation and persistent presence of nonphagocytosed cardiomyocytes (arrows). (C to E). Neutrophils were identified in young mouse infarcts after 24 h (C), 72 h (D), and 7 days (E) of reperfusion. Young animals showed intense neutrophil infiltration of the infarcted myocardium, peaking after 24 h of reperfusion. (F to H) Neutrophil staining in senescent mouse infarcts after 24 h (F), 72 h (G), and 7 days (H) of reperfusion. (I) Senescent mouse infarcts had decreased peak neutrophil infiltration but exhibited timely resolution of the neutrophilic infiltrate (*p < 0.05 vs. young).
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Figure 2 Macrophage Infiltration in the Infarcted Myocardium
(A to C) Mac-2 immunohistochemistry identified macrophages in young mouse infarcts after 24 h (A), 72 h (B), and 7 days (C) of reperfusion. Density of Mac-2 positive cells peaked after 72 h of reperfusion. (D to F) Macrophage staining in senescent mouse infarcts after 24 h (D), 72 h (E), and 7 days (F) of reperfusion. (G) Comparison of macrophage density in senescent and young mouse infarcts (*p < 0.05 vs. young).
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Figure 3 Senescent Animals Exhibited Decreased Myofibroblast Accumulation in the Infarcted Myocardium
Myofibroblasts were identified in young (A) and senescent (B) mouse infarcts as spindle-shaped  -smooth muscle actin immunoreactive cells located outside the vascular media. (C) Senescent mice had significantly lower myofibroblast density in the infarcted myocardium than young animals after 72 h of reperfusion (*p < 0.05).
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Figure 4 Senescent Mice Exhibited Markedly Diminished Collagen Deposition in the Infarct
(A and B) Picrosirius red staining identifies the collagen network in young (A) and senescent (B) mouse infarcts (arrows). Senescent animals had markedly reduced collagen deposition in the infarcted area (C). (D) Senescence was associated with significantly decreased messenger ribonucleic acid (mRNA) expression of the matricellular protein osteopontin in the infarcted heart (**p < 0.01). (E and F) Defective matrix deposition in senescent mouse infarcts was not associated with a reduction in cardiac mRNA expression of transforming growth factor (TGF)-β isoforms.
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Figure 5 Senescent Mouse Cardiac Fibroblasts Show a Blunted Response to TGF-β Stimulation
(A and B) Transforming growth factor (TGF)-β1–stimulated young mouse cardiac fibroblasts showed enhanced expression of phosphorylated Smad2 (p-Smad2), indicating activation of the Smad2/3 pathway, which plays an important role in mediating the pro-fibrotic actions of TGF-β. (C and D) In contrast, fibroblasts isolated from senescent mouse hearts had a blunted and more transient response to TGF-β1 stimulation. (C) Control unstimulated cardiac fibroblasts (**p < 0.01, *p < 0.05 vs. corresponding C, n = 5). GAPDH = glyceraldehyde-3-phosphate dehydrogenase.
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