Browsing by Author "Oakley, Robert H."

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    Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice
    (American Association for the Advancement of Science, 2019-04-16) Oakley, Robert H.; Cruz-Topete, Diana; He, Bo; Foley, Julie F.; Myers, Page H.; Xu, Xiaojiang; Gomez-Sanchez, Celso E.; Chambon, Pierre; Willis, Monte S.; Cidlowski, John A.; Medicine, School of Medicine
    Stress is increasingly associated with heart dysfunction and is linked to higher mortality rates in patients with cardiometabolic disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), both of which are present in cardiomyocytes. To examine the specific and coordinated roles that these receptors play in mediating the direct effects of stress on the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction and died prematurely from heart failure. In contrast, the cardioMRKO mice exhibited normal heart morphology and function. Surprisingly, despite the presence of myocardial stress, the cardioGRMRdKO mice were resistant to the cardiac remodeling, left ventricular dysfunction, and early death observed in the cardioGRKO mice. Gene expression analysis revealed the loss of gene changes associated with impaired Ca2+ handling, increased oxidative stress, and enhanced cell death and the presence of gene changes that limited the hypertrophic response and promoted cardiomyocyte survival in the double knockout hearts. Re-expression of MR in cardioGRMRdKO hearts reversed many of the cardioprotective gene changes and resulted in cardiac failure. These findings reveal a critical role for balanced cardiomyocyte GR and MR stress signaling in cardiovascular health. Therapies that shift stress signaling in the heart to favor more GR and less MR activity may provide an improved approach for treating heart disease.
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    Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice
    (Biomed Central, 2018-09-21) Oakley, Robert H.; Campen, Matthew J.; Paffett, Michael L.; Chen, Xin; Wang, Zhongjing; Parry, Traci L.; Hillhouse, Carolyn; Cidlowski, John A.; Willis, Monte S.; Pathology and Laboratory Medicine, School of Medicine
    BACKGROUND: We recently identified a role for the muscle-specific ubiquitin ligase MuRF1 in right-sided heart failure secondary to pulmonary hypertension induced by chronic hypoxia (CH). MuRF1-/- mice exposed to CH are resistant to right ventricular (RV) dysfunction whereas MuRF1 Tg + mice exhibit impaired function indicative of heart failure. The present study was undertaken to understand the underlying transcriptional alterations in the RV of MuRF1-/- and MuRF1 Tg + mice. METHODS: Microarray analysis was performed on RNA isolated from the RV of MuRF1-/-, MuRF1 Tg+, and wild-type control mice exposed to CH. RESULTS: MuRF1-/- RV differentially expressed 590 genes in response to CH. Analysis of the top 66 genes (> 2-fold or < - 2-fold) revealed significant associations with oxidoreductase, transcription regulation, and transmembrane component annotations. The significant genes had promoters enriched for HOXD12, HOXC13, and RREB-1 protein transcription factor binding sites. MuRF1 Tg + RV differentially expressed 150 genes in response to CH. Analysis of the top 45 genes (> 3-fold or < - 3-fold) revealed significant associations with oxidoreductase-metabolic, glycoprotein-transmembrane-integral proteins, and alternative splicing/splice variant annotations. The significant genes were enriched for promoters with ZIC1 protein transcription factor binding sites. CONCLUSIONS: The differentially expressed genes in MuRF1-/- and MuRF1 Tg + RV after CH have common functional annotations related to oxidoreductase (including antioxidant) and transmembrane component functions. Moreover, the functionally-enhanced MuRF1-/- hearts regulate genes related to transcription, homeobox proteins, and kinases/phosphorylation. These studies also reveal potential indirect effects of MuRF1 through regulating Rreb-1, and they reveal mechanisms by which MuRF1 may transcriptionally regulate anti-oxidant systems in the face of right heart failure.