Abstract
BackgroundInsulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic inflammation and damages the vascular endothelium. Phosphodiesterase-5 inhibitors restore NO signaling and may reduce circulating inflammatory markers, and improve metabolic parameters through a number of mechanisms. We hypothesized that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice.MethodsTwenty leptin receptor null (db/db) mice underwent treatment with TAD (1 mg/Kg) or 10% DMSO for 28 days. Body weight and fasting plasma glucose levels were determined weekly. Upon completion, hearts were isolated and subjected to 30 min global ischemia followed by 60 min reperfusion in a Langendorff model. Plasma samples were taken for cytokine analysis and fasting triglyceride levels. Infarct size was measured using computer morphometry of tetrazolium stained sections. Additionally, ventricular cardiomyocytes were isolated and subjected to 40 min of simulated ischemia and reoxygenation. Necrosis was determined using trypan blue exclusion and LDH release assay and apoptosis was assessed by TUNEL assay after 1 h or 18 h of reoxygenation, respectively.ResultsTreatment with TAD caused a reduction in infarct size in the diabetic heart (23.2±1.5 vs. 47.8±3.7%, p<0.01, n = 6/group), reduced fasting glucose levels (292±31.8 vs. 511±19.3 mg/dL, p<0.001) and fasting triglycerides (43.3±21 vs. 129.7±29 mg/dL, p<0.05) as compared to DMSO, however body weight was not significantly reduced. Circulating tumor necrosis factor-α and interleukin-1β were reduced after treatment compared to control (257±16.51 vs. 402.3±17.26 and 150.8±12.55 vs. 264±31.85 pg/mL, respectively; P<0.001) Isolated cardiomyocytes from TAD-treated mice showed reduced apoptosis and necrosis.ConclusionWe have provided the first evidence that TAD therapy ameliorates circulating inflammatory cytokines and chemokines in a diabetic animal model while improving fasting glucose levels and reducing infarct size following ischemia-reperfusion injury in the heart.
Highlights
The prevalence of diabetes in the United States in increasing at an astronomical rate and the American Diabetes Association currently estimates that 8.3% of the population has diabetes and nearly 79 million people have insulin resistance and are at risk for developing diabetes [1]
The increased incidence of these complications has been attributed to higher levels of inflammatory cytokines, chronic hyperglycemia leading to formation of advanced glycation end products (AGEs) and elevated levels of oxidative stress leading to endothelial dysfunction
Fasting plasma glucose levels and body weight were evaluated weekly whereas plasma triglyceride levels were measured upon completion of therapy
Summary
The prevalence of diabetes in the United States in increasing at an astronomical rate and the American Diabetes Association currently estimates that 8.3% of the population has diabetes and nearly 79 million people have insulin resistance and are at risk for developing diabetes [1]. A number of clinical studies have shown that hyperglycemia and increased AGEs are key factors in potentiating vascular inflammation and increasing levels of reactive oxygen species (ROS) and oxidative stress [4,5]. This vascular milieu of elevated inflammation, impaired NO bioavailability, and oxidative stress plays an integral role in the progression of atherosclerosis and subsequently acute coronary syndromes culminating in significant morbidity and mortality of the diabetic patient [6]. Insulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic inflammation and damages the vascular endothelium. We hypothesized that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice
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