Diet-induced obesity suppresses sevoflurane preconditioning against myocardial ischemia–reperfusion injury: role of AMP-activated protein kinase pathway

Abstract

Obesity is a major risk factor for coronary artery disease, but its impact on anesthetic-induced cardioprotective actions is unexplored. We tested whether obesity inhibits anesthetic sevoflurane-induced preconditioning and whether this effect is mediated via the AMP-activated protein kinase (AMPK) signaling pathway. Sprague-Dawley rats were fed a high-fat (HF, 45% kcal as fat) or low-fat (LF, 10% kcal as fat) diet for 12 weeks. HF-fed rats developed metabolic disturbances including visceral obesity, hyperinsulinemia, hyperleptinemia and dyslipidemia. HF- or LF-fed rats subjected to 25 min of myocardial ischemia followed by 120 min of reperfusion were assigned to the following groups: control, sevoflurane preconditioning, sevoflurane plus AMPK inhibitor ara-A or AMPK activator A769662 alone. Infarct size was similar between the two control groups. Sevoflurane preconditioning significantly reduced infarct size in LF-fed rats but failed to induce cardioprotection in HF-fed rats. Phosphorylation of AMPK and endothelial nitric oxide synthase, as well as myocardial nitrite and nitrate, were also increased by sevoflurane preconditioning in LF-fed rats but not in HF-fed rats. Pretreatment with ara-A inhibited phosphorylation of AMPK and reversed sevoflurane preconditioning-induced cardioprotection in LF-fed rats, whereas it had no effects in HF-fed rats. In addition, sevoflurane preconditioning failed to enhance reactive oxygen species (ROS) generation in the myocardium of HF-fed rats compared with LF-fed rats. Direct activation of AMPK with A769662 equally increased phosphorylation of AMPK and reduced infarct size in both LF- and HF-fed rats. The results suggest that diet-induced obesity suppresses sevoflurane preconditioning-induced cardioprotective action, probably due to a diminished effect of sevoflurane preconditioning on activation of the ROS-mediated AMPK signaling pathway.

Sevoflurane postconditioning against cerebral ischemic neuronal injury is abolished in diet-induced obesity: Role of brain mitochondrial KATP channels

“…Multiple intracellular mechanisms, including the activation of protein kinase C, mitogen-activated protein kinase, adenosine receptors and mitoK ATP channels, have been indicated to be involved in anesthetic preconditioning-induced cardioprotection and neuroprotection (8,10,20). It is widely accepted that the activation/opening of mitoK ATP channels is a significant mechanism for ischemic preconditioning-induced protection in various organs and for ischemic postconditioning-induced cardioprotection (10).…”

“…Therefore, anesthetic postconditioning by modulation of reperfusion rather than ischemia may be more clinically useful for cardioprotection, as well as for neuroprotection. It has been demonstrated that pathological situations, including obesity, may affect the effectiveness of well-established cardioprotective strategies (7,8). However, the majority of studies regarding anesthetic postconditioning-induced neuroprotection have been conducted in healthy animals (4,9,10).…”

Ischaemic conditioning: intervening to protect; before, after, and at a distance

“…However, uncertainty remains. Preconditioning using volatile anaesthetic agents appears to work less well in animal models of hyperglycaemia and hypercholesterolaemia [5,6], precisely those situations in which we perceive the greatest perioperative risk. However, do rabbits and cardiac myocytes adequately model the metabolic syndrome?…”

Roles of Obese-Insulin Resistance and Anti-Diabetic Drugs on the Heart with Ischemia-Reperfusion Injury

“…Both genetic deletion and diet-induced obesity are widely used to replicate characteristics of metabolic syndrome in humans [6,18,20,23,25,27,[30][31][32][33]. According to the International Diabetes Federation (IDF), the metabolic syndrome is defined as a person having central obesity (a waist circumference≥94 cm for men, and≥80 cm for women) plus any two of the following four factors including raised triglyceride level (≥150 mg/ dL), reduced HDL cholesterol level (<40 mg/dL in males, and <50 mg/dL in females), raised blood pressure (systolic BP≥ 130 mmHg, Diastolic BP≥85 mmHg), and raised fasting plasma glucose levels (≥100 mg/dL).…”

“…Either high-fat or high-carbohydrate food is usually chosen to induce obese-insulin resistance. Previous studies demonstrated that a high-fat diet (HFD) could increase body weight, plasma insulin, leptin, and cholesterol levels [13,22,33,34], indicating the development of obese-insulin resistance. Insulin sensitivity is also impaired in HFD-fed rats as indicated by increased blood glucose levels during an oral-glucose tolerance test (OGTT) [22].…”