Cardiomyocite Contractility,Calcium handling and Endothelial Function in a mouse model of Type II Diabetes and the Metabolic Syndrome

Diabetes, obesity and dyslipidemia are associated with a significant increase in cardiovascular morbidity and mortality, caused by cardiomyopathy, vasculopathy and their consequences. The prevalence of affected patients is still increasing, resulting in a major health care problem.14.0pt;margin-left:0cm;text-align:justify;line-height:150%;text-autospace:ideograph-numeric" align="left">The existence of a primary diabetic cardiomyopathy, in the absence of an ischemic or hypertensive cardiomyopathy is at least partially related to alterations in cardiomyocyteproperties. Although it has been shown in vivo that cardiac dysfunctionis aggravated in the metabolic syndrome and characterized by additionalfeatures, -.1pt">changes in intrinsic properties of cardiomyocytes have not been studied in mice with the metabolic syndrome (MetS). 14.0pt;margin-left:0cm;text-align:justify;line-height:150%;text-autospace:ideograph-numeric" align="left">Diabeticangiopathy is characterized by abnormalities in vascular wall morphology and altered vascular reactivity. It is currently unclear whether the dyslipidemia and hypertension, associated with diabetes type II in MetS, worsen these diabetes-induced alterations in vascular function.-.1pt"> 14.0pt;margin-left:0cm;text-align:justify;line-height:150%;text-autospace:ideograph-numeric" align="left">-.1pt">Concerning therapy, 150%">hypocaloric diet and ACE-inhibitors arecurrently the golden standard in the treatment of cardiovascular complications in patients with diabetes mellitus type II and the metabolic syndrome. .5pt">However, most studies are performed with both entities in one group, exhibiting a large pathological and clinical variance-.1pt">. ideograph-numeric" align="left">-.1pt">This study was designed tline-height:150%;letter-spacing:-.1pt">o gain further insight into the mechanisms contributing to cardiovascular dysfunction in the metabolic syndrome and to.5pt"> study more in detail the effect of ACE-inhibitors and hypocaloric dieton cardiovascular function in d150%">iabetes type II and the metabolic syndrome.5pt">, as separate entities. ideograph-numeric" align="left">Cardiomyocyte function and Ca2+ handling in a mouse model of the metabolic syndrome. We have shown that cardiomyocyte function and Ca2+ handling are impaired in DKO mice (the used model of the metabolic syndrome), associated with reduced contractile reserve, compared to ob/ob mice. ACE-inhibition, but not weight reduction, can restore cardiomyocyte relaxation and β-adrenergic responsiveness. These data indicate that the in vivo features of cardiomyopathy in the metabolic syndrome can at least partially be explained by alterations in intrinsic cardiomyocyte properties and Ca2+ handling. Secondly, they indicate that dyslipidemia and/or hypertension in typeII diabetic mice aggravate cardiomyocyte dysfunction.14.0pt;margin-left:0cm;text-align:justify;line-height:150%;text-autospace:ideograph-numeric" align="left">Vascular reactivity in a mouse model of themetabolic syndrome.DKO mice show a more pronounced impairment of acetylcholine-induced vasorelaxation, compared to ob/ob. This effect is mainly NO-mediated and can be restored by ACE-inhibition and hypocaloric diet. In contrast, response to bradykinin is equally reduced in both genotypes and is not influenced by ACE-inhibition. These data suggest that dyslipidemia and hypertension aggravate NO-mediated endothelium-dependentrelaxation in type II diabetic mice, reversible by ACE-inhibition and diet. In contrast, these features prevent further worsening of bradykinin-induced vasorelaxation in type II diabetic mice. This effect might be mediated via endothelial COX-2 and can not be restored by ACE-inhibition.14.0pt;margin-left:0cm;text-align:justify;line-height:150%;text-autospace:ideograph-numeric" align="left">Taken together, this study shows that dyslipidemia and hypertension aggravate cardiovascular dysfunction in vitro in type II diabetic mice. ACE-inhibiton and hypocaloric diet can improve this impaired cardiovascular function.status: publishe