Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Cardiomyocyte MR dependent DOC/salt-mediated gene regulation

ABSTRACT: Genome wide gene expression analysis of mRNA siolated from whole heart tissue from wild type and cardiomyocyte selective MR null mice. The role of mineralocorticoid receptors (MR) in specific cell types of the myocardium in cardiac remodeling remains unknown. We investigated MR in cardiomyocytes in DOC/salt-induced cardiac pathology. Cardiomyocyte MR-null mice (CM-MRKO) and control mice (WT) were given DOC/salt and cardiac responses were examined at 8 days and 8 weeks. Cardiac function in untreated mice wild type and CM-MRKO mice was determined by Langendorf and showed no differences. At 8 days CM-MRKO showed equivalent monocyte/macrophage recruitment to wild type mice in response to DOC/salt treatment. Profibrotic markers were significantly reduced in CM-MRKO hearts at base line and in response to DOC/salt. In contrast, at 8 weeks CM-MRKO mice showed no DOC/salt-induced increase in inflammatory cell infiltrate, fibrosis or systolic blood pressure (SBP). Similarly, DOC/salt-mediated increases in proinflammatory and profibrotic gene expression were not detected in CM-MRKO mice. Although mRNA levels for fibronectin and collagen III were similar for each genotype, this was not translated into protein expression. Interestingly, untreated CM-MRKO mice showed increased mRNA and protein for decorin and a further increase with DOC/salt. Together, these data suggest a direct role for cardiomyocyte MR in DOC/salt-induced tissue remodelling and SBP regulation. Moreover, a specific profibrotic pathway is dysregulated in CM-MRKO mice, suggesting a potential mechanism for the cardioprotective effects of selective MR deletion in cardiomyocytes. Pool mRNA (equal amounts) from whole heart from 8 animals per group.

ORGANISM(S): Mus musculus

SUBMITTER: Morag Young

PROVIDER: E-GEOD-38869 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. Methods: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. Results: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction—suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular cardiomyocytes corroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts. In vivo rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Conclusions: Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling

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Cardiomyocyte MR dependent DOC/salt-mediated gene regulation

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