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Reperfusion injury is not affected by blockade of P-selectin in the diabetic mouse heart
S P Jones1, W G Girod, D N Granger
1Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport, Louisiana 71130, USA.
Abstract:
We examined the mechanisms responsible for myocardial ischemia-reperfusion (MI-R) injury in a well-characterized animal model of type II diabetes mellitus. Diabetic (db/db) mice and their littermate nondiabetic controls were subjected to 30 min of left anterior descending coronary artery occlusion and 2 h of reperfusion. Diabetic and nondiabetic mice experienced similar-sized areas at risk per left ventricle: 50.4 +/- 2.0 and 53.4 +/- 4.1%, respectively. However, myocardial necrosis (percentage of area at risk) was significantly greater (P < 0.001) in diabetic than in nondiabetic animals: 56.3 +/- 2.8 and 27.2 +/- 3.1%, respectively. Histological examination revealed significantly (P < 0.05) more neutrophils (PMNs) in the diabetic than in the nondiabetic hearts. Coronary endothelial expression of P-selectin was determined using radiolabeled monoclonal antibodies (MAbs). MI-R elicited a more intense (P < 0.05) upregulation of P-selectin in the ischemic zone of diabetic than of nondiabetic myocardium: 0.310 +/- 0.034 and 0. 161 +/- 0.042 microgram MAb/g tissue. Immunoneutralization of P-selectin (RB40.34) reduced PMN accumulation in the diabetic myocardium but failed to reduce the extent of myocardial necrosis. Conversely, administration of an MAb directed against CD18 (GAME46) reduced PMN infiltration and attenuated the infarct size in the diabetic hearts. These results suggest that the diabetic heart is more susceptible to ischemia-reperfusion injury than normal myocardium. Furthermore, the mechanism of this injury may not be critically dependent on P-selectin in diabetic hearts.
Insights
Diabetic hearts show increased susceptibility to ischemia-reperfusion injury. While P-selectin is upregulated, targeting CD18 is more effective in reducing injury and neutrophil infiltration in diabetic myocardium.
Area of Science:
- Cardiovascular Science
- Diabetology
- Pathophysiology
Background:
- Myocardial ischemia-reperfusion (MI-R) injury is a significant clinical concern.
- Type II diabetes mellitus exacerbates cardiovascular disease and complicates MI-R outcomes.
- Understanding the specific mechanisms in diabetic hearts is crucial for targeted therapies.
Purpose of the Study:
- To investigate the mechanisms underlying enhanced myocardial ischemia-reperfusion (MI-R) injury in a type II diabetes mellitus animal model.
- To compare the response to MI-R in diabetic (db/db) mice versus nondiabetic controls.
- To elucidate the role of P-selectin and CD18 in diabetic MI-R injury.
Main Methods:
- Utilized a murine model of type II diabetes (db/db mice) subjected to coronary artery occlusion and reperfusion.
- Quantified myocardial necrosis and neutrophil (PMN) infiltration via histological analysis.
- Assessed P-selectin expression using radiolabeled monoclonal antibodies (MAbs).
- Investigated the effects of immunoneutralization of P-selectin and CD18.
Main Results:
- Diabetic hearts exhibited significantly greater myocardial necrosis (56.3%) compared to nondiabetic hearts (27.2%) after MI-R.
- Increased neutrophil (PMN) accumulation and P-selectin expression were observed in diabetic myocardium.
- P-selectin blockade reduced PMN accumulation but not necrosis; CD18 blockade reduced both PMN infiltration and infarct size.
Conclusions:
- The diabetic heart is demonstrably more susceptible to ischemia-reperfusion injury.
- Neutrophil infiltration plays a key role in this exacerbated injury.
- Therapeutic strategies targeting CD18, rather than P-selectin alone, may be more effective in mitigating diabetic MI-R injury.