Unknown,Transcriptomics,Genomics,Proteomics

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Overexpression of Integrin Î±11 Induces Cardiac Fibrosis in Mice

ABSTRACT: The integrin Î±11-overexpressing transgenic mouse strain was generated to further understand the function of Î±11, after generation of our integrin Î±11-KO strain. Analysis of the strain showed that integrin Î±11 was highly expressed in heart, which correlated with a fibrotic heart phenotype. To understand the molecular mechanisms underlying this phenotype, we then performed Microarray to investigate the differentially expressed genes between the WT and TG mice (Î±11-overexpressing mice) which may result from integrin Î±11 overexpression. The microarray was performed on RNA-isolates from the heart apex of 1-year-old WT (n=4) and Î±11-TG (n=6) mice. Total RNA isolation was performed using RNeasy Fibrous Tissue Mini Kit (Qiagen) in accordance with the manufacturerâs protocol. Quality of RNA samples was assessed using Agilent Bioanalyzer 2100. Microarray was carried out at the Norwegian Microarray Consortium/University of Bergen Microarray Core Facility at Haukeland University Hospital. Illumina Bead Array Technology was used, and the raw microarray data was quality examined in GenomeStudio. Differentially expressed genes were analysed using the Ingenuity Pathways Analysis (IPA) software (Ingenuity Systems, Redwood City, CA).

ORGANISM(S): Mus musculus

SUBMITTER: Rita Holdhus

PROVIDER: E-MTAB-5040 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The Ca2+/calmodulin-dependent kinase II is expressed in smooth muscle and believed to mediate intracellular calcium handling and calcium-dependent gene transcription. CaMKII is activated by Angiotensin-II. The multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by Angiotensin-II (Ang-II) in vascular smooth muscle cells (VSMC), but its impact on hypertension remains unknown. In our transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), the blood pressure response to chronic Ang-II infusion was significantly reduced as compared to littermate controls. Surprisingly, examination of blood pressure and heart rate under ganglionic blockade revealed a key role for VSMC CaMKII in efferent sympathetic outflow in response to Ang II hypertension. Consistently, the efferent splanchnic nerve activity and plasma phenylephrine concentrations were significantly lower in TG SM-CaMKIIN mice as compared to littermates. Moreover, the aortic depressor nerve activity was reset in hypertensive wild type animals, but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor wall activity may be responsible for the blood pressure difference in Ang-II hypertension. The pulse wave velocity, a measure of vascular wall stiffness in vivo, was increased in aortas of hypertensive compared to normotensive WT animals. However, Ang-II infusion did not alter the pulse wave velocity in transgenic mice, suggesting that CaMKII in VSMC controls structural smooth muscle genes. Accordingly, analysis of gene expression changes in aortas from wild type and TG SM-CaMKIIN hypertensive mice demonstrated that CaMKII inhibition mainly altered the expression of muscle contractile proteins. In contrast, TG SM-CaMKIIN aortas were protected from the Ang-II induced upregulation of genes linked to proliferation, suggesting that CaMKII inhibition prevents the Ang-II-induced reprogramming of smooth muscle cell gene expression towards a proliferative phenotype. 5 WT C57Bl/6 and 5 mice that express the Ca2+/calmodulin-dependent kinase II peptide inhibitor CaMKIIN in smooth muscle only (TG SM-CaMKIIN) were infused with 1.25 ug/kg/min Angiotensin-II by osmotic minipump for 14 days. 5 WT and 5 transgenic mice infused with normal saline served as controls. The mice were sacrificed on day 14 and the thoracic aortas isolated. RNA was isolated and pooled for the following groups: WT (wild type), C (TG SM-CaMKIIN), WT-A (WT with Angiotensin-II), C-A (TG SM-CaMKIIN + Angiotensin-II)

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Overexpression of Integrin Î±11 Induces Cardiac Fibrosis in Mice

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