Abstract
BackgroundDiabetic patients, through incompletely understood mechanisms, endure exacerbated ischemic heart injury compared to non-diabetic patients. Intermedin (IMD) is a novel calcitonin gene-related peptide (CGRP) superfamily member with established cardiovascular protective effects. However, whether IMD protects against diabetic myocardial ischemia/reperfusion (MI/R) injury is unknown.MethodsDiabetes was induced by streptozotocin in Sprague–Dawley rats. Animals were subjected to MI via left circumflex artery ligation for 30 minutes followed by 2 hours R. IMD was administered formally 10 minutes before R. Outcome measures included left ventricular function, oxidative stress, cellular death, infarct size, and inflammation.ResultsIMD levels were significantly decreased in diabetic rats compared to control animals. After MI/R, diabetic rats manifested elevated intermedin levels, both in plasma (64.95 ± 4.84 pmol/L, p < 0.05) and myocardial tissue (9.8 ± 0.60 pmol/L, p < 0.01) compared to pre-MI control values (43.62 ± 3.47 pmol/L and 4.4 ± 0.41). IMD administration to diabetic rats subjected to MI/R decreased oxidative stress product generation, apoptosis, infarct size, and inflammatory cytokine release (p < 0.05 or p < 0.01).ConclusionsBy reducing oxidative stress, inflammation, and apoptosis, IMD may represent a promising novel therapeutic target mitigating diabetic ischemic heart injury.
Highlights
Diabetic patients, through incompletely understood mechanisms, endure exacerbated ischemic heart injury compared to non-diabetic patients
Diabetic animals manifested significantly decreased IMD levels, while myocardial ischemia/reperfusion (MI/R) increased IMD levels IMD levels were significantly decreased in diabetic rats compared to control animals
We demonstrate myocardial infarction (MI)/R increased caspase-3 activity and Bax protein expression in diabetic animals compared to control, which was attenuated by IMD administration
Summary
Through incompletely understood mechanisms, endure exacerbated ischemic heart injury compared to non-diabetic patients. Intermedin (IMD) is a novel calcitonin gene-related peptide (CGRP) superfamily member with established cardiovascular protective effects. Whether IMD protects against diabetic myocardial ischemia/reperfusion (MI/R) injury is unknown. Females are at greater risk for acute myocardial infarction (MI) compared to male diabetic patients [3]. Diabetic patients are more susceptible to myocardial ischemia/reperfusion (MI/R) injury than non-diabetics, with greater mortality and resultant heart failure [4,5,6]. Select pharmacologic agents reducing myocardial injury in non-diabetic animal models are ineffective in diabetic animal models [9]. Intermedin (IMD), known as adrenomedullin 2 (ADM2), belongs to the calcitonin gene-related peptide (CGRP) superfamily. Peptide fragments (IMD1–47, IMD8–47, and IMD1–53) are generated from pre-proIMD by proteolytic cleavage [10]
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