Unknown,Transcriptomics,Genomics,Proteomics

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Atorvastatin Reduces Î²-Adrenergic Dysfunction in Rats with Diabetic Cardiomyopathy

ABSTRACT: Background: In the diabetic heart the Î²-adrenergic response is altered partly by down-regulation of the Î²1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the Î²3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to âpleiotropicâ effects. The objective of our study was to investigate the role of statin treatment on Î²-adrenergic dysfunction in diabetic rat cardiomyocytes. Methods: Î²-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline Â± SD. Results: Atorvastatin restored the impaired positive inotropic effect of Î²-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the Î²-adrenergic pathway and corrected the protein expression of Î²1-adrenoceptor and Î²1/Î²3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the Î²-adrenoceptor response. Conclusions: Atorvastatin restored the positive inotropic effect of the Î²-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the Î²-adrenergic signaling pathway, particularly through the NOS pathway.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Nicolas Cagnard

PROVIDER: E-MTAB-5594 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:AIMS/HYPOTHESIS: Pregnancies complicated by diabetes have a higher risk of adverse outcomes for mothers and children, including predisposition to disease later in life, such as metabolic syndrome and hypertension. We hypothesized that adverse outcomes from diabetic pregnancies may be linked to compromised placental function. Our goal in this study was to identify cellular and molecular abnormalities in diabetic placenta. METHODS: Using a mouse model of diabetic pregnancy, placental gene expression was assayed at midgestation and cellular composition was analyzed at various stages. Genome-wide expression profiling was validated by quantitative PCR, and tissue localization studies were performed to identify cellular correlates of altered gene expression in diabetic placenta. RESULTS: We detected significantly altered gene expression in diabetic placenta for genes expressed in the maternal as well as those in the embryonic compartments. We also found altered cellular composition of the decidual compartment. Furthermore, the junctional and labyrinth layers were reduced in diabetic placenta, accompanied by aberrant differentiation of spongiotrophoblast cells. CONCLUSIONS/INTERPRETATION: Diabetes during pregnancy alters transcriptional profiles in the murine placenta, affecting cells of both embryonic and maternal origin, and involving several genes not previously implicated in diabetic pregnancies. The molecular changes and abnormal differentiation of multiple cell types precede impaired growth of junctional zone and labyrinth, and placenta overall. Whether these changes represent direct responses to hyperglycaemia or physiological adaptations, they are likely to play a role in pregnancy complications and outcomes, and have implications for developmental origins of adult disease. The STZ diabetic mouse model was used to investigate gene expression changes in diabetic placentae at E10.5. Placentae were dissected from 5 different FVB dams at embryonic day 10.5 under diabetic conditions and from 5 control dams. Gene expression profiles from five individual placentae from independent pregnancies per group were compared.

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Atorvastatin Reduces Î²-Adrenergic Dysfunction in Rats with Diabetic Cardiomyopathy

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