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Ischemia-reperfusion injury leads to distinct temporal cardiac remodeling in normal versus diabetic mice.

Eguchi M, Kim YH, Kang KW, Shim CY, Jang Y, Dorval T, Kim KJ, Sweeney G - PLoS ONE (2012)

Bottom Line: We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV) in both control and diabetic mice.However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-((18)F)fluoro-D-glucose.This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur Korea, Seoul, South Korea.

ABSTRACT
Diabetes is associated with higher incidence of myocardial infarction (MI) and increased propensity for subsequent events post-MI. Here we conducted a temporal analysis of the influence of diabetes on cardiac dysfunction and remodeling after ischemia reperfusion (IR) injury in mice. Diabetes was induced using streptozotocin and IR performed by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for up to 42 days. We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV) in both control and diabetic mice. The longitudinal systolic and diastolic strain rate were altered after IR, but there were no significant differences between diabetic mice and controls. However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-((18)F)fluoro-D-glucose. Interestingly, after 24 hours reperfusion diabetic mice showed a reduced infarct size and less apoptosis indicated by TUNEL analysis in heart sections. This may be explained by increased levels of autophagy detected in diabetic mice hearts. Similar increases in IR-induced macrophage infiltration detected by CD68 staining indicated no change in inflammation between control and diabetic mice. Over time, control mice subjected to IR developed mild left ventricular dilation whereas diabetic mice exhibited a decrease in both end diastolic left ventricular volume and LVESV with a decreased intraventricular space and thicker left ventricular wall, indicating concentric hypertrophy. This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group. In summary, we demonstrate that diabetes principally influences distinct IR-induced chronic changes in cardiac function and remodeling, while a smaller infarct size and elevated levels of autophagy with similar cardiac function are observed in acute phase.

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Effects of IR injury on cardiac cell death.A) Hearts were isolated at 24 hr of reperfusion and stained with TTC for the measurement of infarct area. Viable part of the heart appears red and the infarct area white. B) Quantification of the infarct area shows that the infarct area is significantly smaller in STZ compared to VEH hearts. C) Apoptotic cells were identified using TUNEL method. TUNEL-positive nuclei are shown in green and total nuclei in DAPI, blue. D) Quantification of TUNEL positive nuclei reveals that the number of apoptotic cells is much lower in the hearts isolated from STZ animals. Analysis of autophagy-related proteins (E) indicates that autophagy is upregulated in STZ heart. The level of LC3II was significantly higher in the STZ heart compared to VEH and the increase in autophagy was confirmed by the increase in cathepsin D and decrease in p62. (n≥3) and * indicates that p<0.05 compared to VEH.
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pone-0030450-g003: Effects of IR injury on cardiac cell death.A) Hearts were isolated at 24 hr of reperfusion and stained with TTC for the measurement of infarct area. Viable part of the heart appears red and the infarct area white. B) Quantification of the infarct area shows that the infarct area is significantly smaller in STZ compared to VEH hearts. C) Apoptotic cells were identified using TUNEL method. TUNEL-positive nuclei are shown in green and total nuclei in DAPI, blue. D) Quantification of TUNEL positive nuclei reveals that the number of apoptotic cells is much lower in the hearts isolated from STZ animals. Analysis of autophagy-related proteins (E) indicates that autophagy is upregulated in STZ heart. The level of LC3II was significantly higher in the STZ heart compared to VEH and the increase in autophagy was confirmed by the increase in cathepsin D and decrease in p62. (n≥3) and * indicates that p<0.05 compared to VEH.

Mentions: To examine the effects of STZ-diabetes on the extent of myocardial injury induced by IR, isolated hearts were stained with TTC to identify the infarct area size. Infarct area was significantly reduced in STZ animals compared to VEH animals at 24 hours of reperfusion time as shown visually and quantitatively in figure 3A and B, respectively. We also studied the extent of cell death using TUNEL staining of heart sections prepared after 24 hours of reperfusion. Consistent with infarct area data, the number of apoptotic cells was significantly lower in the STZ mouse heart compared to VEH (figure 3C,D).


Ischemia-reperfusion injury leads to distinct temporal cardiac remodeling in normal versus diabetic mice.

Eguchi M, Kim YH, Kang KW, Shim CY, Jang Y, Dorval T, Kim KJ, Sweeney G - PLoS ONE (2012)

Effects of IR injury on cardiac cell death.A) Hearts were isolated at 24 hr of reperfusion and stained with TTC for the measurement of infarct area. Viable part of the heart appears red and the infarct area white. B) Quantification of the infarct area shows that the infarct area is significantly smaller in STZ compared to VEH hearts. C) Apoptotic cells were identified using TUNEL method. TUNEL-positive nuclei are shown in green and total nuclei in DAPI, blue. D) Quantification of TUNEL positive nuclei reveals that the number of apoptotic cells is much lower in the hearts isolated from STZ animals. Analysis of autophagy-related proteins (E) indicates that autophagy is upregulated in STZ heart. The level of LC3II was significantly higher in the STZ heart compared to VEH and the increase in autophagy was confirmed by the increase in cathepsin D and decrease in p62. (n≥3) and * indicates that p<0.05 compared to VEH.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3275560&req=5

pone-0030450-g003: Effects of IR injury on cardiac cell death.A) Hearts were isolated at 24 hr of reperfusion and stained with TTC for the measurement of infarct area. Viable part of the heart appears red and the infarct area white. B) Quantification of the infarct area shows that the infarct area is significantly smaller in STZ compared to VEH hearts. C) Apoptotic cells were identified using TUNEL method. TUNEL-positive nuclei are shown in green and total nuclei in DAPI, blue. D) Quantification of TUNEL positive nuclei reveals that the number of apoptotic cells is much lower in the hearts isolated from STZ animals. Analysis of autophagy-related proteins (E) indicates that autophagy is upregulated in STZ heart. The level of LC3II was significantly higher in the STZ heart compared to VEH and the increase in autophagy was confirmed by the increase in cathepsin D and decrease in p62. (n≥3) and * indicates that p<0.05 compared to VEH.
Mentions: To examine the effects of STZ-diabetes on the extent of myocardial injury induced by IR, isolated hearts were stained with TTC to identify the infarct area size. Infarct area was significantly reduced in STZ animals compared to VEH animals at 24 hours of reperfusion time as shown visually and quantitatively in figure 3A and B, respectively. We also studied the extent of cell death using TUNEL staining of heart sections prepared after 24 hours of reperfusion. Consistent with infarct area data, the number of apoptotic cells was significantly lower in the STZ mouse heart compared to VEH (figure 3C,D).

Bottom Line: We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV) in both control and diabetic mice.However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-((18)F)fluoro-D-glucose.This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur Korea, Seoul, South Korea.

ABSTRACT
Diabetes is associated with higher incidence of myocardial infarction (MI) and increased propensity for subsequent events post-MI. Here we conducted a temporal analysis of the influence of diabetes on cardiac dysfunction and remodeling after ischemia reperfusion (IR) injury in mice. Diabetes was induced using streptozotocin and IR performed by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for up to 42 days. We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV) in both control and diabetic mice. The longitudinal systolic and diastolic strain rate were altered after IR, but there were no significant differences between diabetic mice and controls. However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-((18)F)fluoro-D-glucose. Interestingly, after 24 hours reperfusion diabetic mice showed a reduced infarct size and less apoptosis indicated by TUNEL analysis in heart sections. This may be explained by increased levels of autophagy detected in diabetic mice hearts. Similar increases in IR-induced macrophage infiltration detected by CD68 staining indicated no change in inflammation between control and diabetic mice. Over time, control mice subjected to IR developed mild left ventricular dilation whereas diabetic mice exhibited a decrease in both end diastolic left ventricular volume and LVESV with a decreased intraventricular space and thicker left ventricular wall, indicating concentric hypertrophy. This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group. In summary, we demonstrate that diabetes principally influences distinct IR-induced chronic changes in cardiac function and remodeling, while a smaller infarct size and elevated levels of autophagy with similar cardiac function are observed in acute phase.

Show MeSH
Related in: MedlinePlus