Intervention of rosiglitazone on myocardium Glut-4 mRNA expression during ischemia–reperfusion injury in cardio-pulmonary bypass in dogs

Abstract

During cardiac pulmonary bypass (CPB), myocardial ischemia-reperfusion (I/R) induces heart glucose metabolism impairment. Our previous research showed that the decreased glucose utilization is due to decreased glucose transporter-4 (Glut-4) expression and translocation to myocyte surface membranes. This study further examined whether rosiglitazone, a synthetic agonist of peroxisome proliferator-activated receptor γ, could intervene glucose metabolism by regulating Glut-4 mRNA during I/R in dogs. Cardiac ischemia was induced by cardiopulmonary bypass for 30 or 120 min. Plasma insulin and glucose concentrations were measured at pre-bypass (control), aortic cross-clamp off (I/R) at 15, 45, and 75 min. The left ventricle biopsies were taken for the expression of Glut-4 mRNA by real-time RT-PCR. In dogs receiving 120 min ischemia, coronary arterial, venous glucose concentrations, plasma insulin levels, and insulin resistant index (IRI) were increased, but the expression of Glut-4 mRNA was decreased obviously at 15 min of reperfusion, and recovered gradually. On the other hand, these changes were relatively mild in dogs treated with rosiglitazone in cardioplegic solution and expression of Glut-4 mRNA was increased remarkably. It is concluded that the decrease in total amount of Glut-4 mRNA expression could be one of the important molecular mechanisms, which causes the myocardium insulin resistance. The longer the ischemia period, the decrease in amount of Glut-4 mRNA was more dramatic. Adding rosiglitazone into the cardioplegic solution during I/R can increase the amount of Glut-4 mRNA expression, mitigate the myocardium insulin resistance and improve the myocardium I/R injury during CPB.

Heart Failure and Loss of Metabolic Control

“…137 More recently, TZD administration was reported to increase GLUT4 expression, improve insulin sensitivity, and enhance cardiac function in dogs. 138 However, clinical use of PPAR-γ agonists to treat heart failure, cardiac ischemia/reperfusion, and even diabetes has been hindered due to potential cardiac toxicity manifested as fluid retention. 139 …”

Peroxisome proliferator-activated receptor (PPAR) gamma in cardiovascular disorders and cardiovascular surgery

“…During reperfusion following a prolonged ischemia, the expression of glucose transporter-4 was inhibited significantly, leading to decreased glucose uptake, impaired energy metabolism, and cardiac function damage. The addition of rosiglitazone into cardioplegic solution increased expression of glucose transporter-4 at mRNA level and resulted in the attenuation of myocardium damage, alleviation of insulin resistance [115].…”

Activation of AMPK alleviates cardiopulmonary bypass‐induced cardiac injury via ameliorating acute cardiac glucose metabolic disorder

“…Cardiopulmonary bypass (CPB)‐induced cardiac injury is one of the most serious forms of critical illness, which is characterized by stress, hyperglycemia, inflammation, hyperactive metabolic responsiveness, and glucose metabolism disorders . It has been shown that impaired myocardial glucose uptake results in myocardial damage and cardiac dysfunction in myocardial ischemia/reperfusion injury or in diabetes .…”

“…7,8 Cardiopulmonary bypass (CPB)-induced cardiac injury is one of the most serious forms of critical illness, which is characterized by stress, hyperglycemia, inflammation, hyperactive metabolic responsiveness, 9,10 and glucose metabolism disorders. 11 It has been shown that impaired myocardial glucose uptake results in myocardial damage and cardiac dysfunction in myocardial ischemia/ reperfusion injury or in diabetes. 7,12 Moreover, acute myocardial insulin resistance has been shown to play an important role in cardiac dysfunction and increases the complications and mortality in an animal model of severe burn injury.…”

“…Previous study revealed that glucose transporters (GLUTs), such as GLUT4, GLUT1, and GLUT8, were found to exist in the normal heart, 14 and decreased plasma membrane content of GLUT4 contributes to acute myocardial glucose metabolic disorder induced by CPB. 11 In addition, Adenosine 5'-monophosphate-activated protein kinase (AMPK), a key sensor of cellular energy status, plays a major role in the adaptive response to stress by modulating myocardial glucose metabolism. 15 The critical importance of AMPK function in the heart was highlighted by the observation that genetic mutations in the PRKAG2 gene, which encode the γ-2 regulatory subunit of AMPK, gives rise to a novel cardiac glycogenosis syndrome in humans.…”