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  • 1
    Online Resource
    Online Resource
    Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy
    Wiley ; 2023
    In:  Aging Cell Vol. 22, No. 4 ( 2023-04)
    Details
    In: Aging Cell, Wiley, Vol. 22, No. 4 ( 2023-04)
    Abstract: Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle‐specific creatinine kinase ( Ckmm ) promoter or depleted systemically ( Ercc1 −/D mice). Ckmm‐Cre +/− ;Ercc1 −/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm‐Cre +/− ;Ercc1 −/fl mice were structurally and functionally normal, but by 6‐months‐of‐age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue‐specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm‐Cre +/‐ ;Ercc1 −/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm‐Cre +/− ;Ercc1 −/fl and Ercc1 −/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial‐targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.
    Type of Medium: Online Resource
    ISSN: 1474-9718 , 1474-9726
    URL: Issue
    URL: Article
    DOI: 10.1111/acel.v22.4
    DOI: 10.1111/acel.13782
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2099130-7
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Nuclear α1-Adrenergic Receptors Signal Activated ERK Localization to Caveolae in Adult Cardiac Myocytes
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Research Vol. 103, No. 9 ( 2008-10-24), p. 992-1000
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 103, No. 9 ( 2008-10-24), p. 992-1000
    Abstract: We previously identified an α1-AR-ERK (α1A-adrenergic receptor–extracellular signal-regulated kinase) survival signaling pathway in adult cardiac myocytes. Here, we investigated localization of α1-AR subtypes (α1A and α1B) and how their localization influences α1-AR signaling in cardiac myocytes. Using binding assays on myocyte subcellular fractions or a fluorescent α1-AR antagonist, we localized endogenous α1-ARs to the nucleus in wild-type adult cardiac myocytes. To clarify α1 subtype localization, we reconstituted α1 signaling in cultured α1A- and α1B-AR double knockout cardiac myocytes using α1-AR–green fluorescent protein (GFP) fusion proteins. Similar to endogenous α1-ARs and α1A- and α1B-GFP colocalized with LAP2 at the nuclear membrane. α1-AR nuclear localization was confirmed in vivo using α1-AR-GFP transgenic mice. The α1-signaling partners Gαq and phospholipase Cβ1 also colocalized with α1-ARs only at the nuclear membrane. Furthermore, we observed rapid catecholamine uptake mediated by norepinephrine-uptake-2 and found that α1-mediated activation of ERK was not inhibited by a membrane impermeant α1-blocker, suggesting α1 signaling is initiated at the nucleus. Contrary to prior studies, we did not observe α1-AR localization to caveolae, but we found that α1-AR signaling initiated at the nucleus led to activated ERK localized to caveolae. In summary, our results show that nuclear α1-ARs transduce signals to caveolae at the plasma membrane in cardiac myocytes.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.108.176024
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1467838-X
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  • 3
    Online Resource
    Online Resource
    Abstract P193: Nuclear Localization of the α1B-Adrenergic Receptor Subtype Is Required for Hypertrophic Signaling in Cardiac Myocytes
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Research Vol. 109, No. suppl_1 ( 2011-12-09)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 109, No. suppl_1 ( 2011-12-09)
    Abstract: We previously demonstrated that α1-adrenergic receptors (α1-ARs) in the heart are required for physiologic hypertrophy during development and prevent a maladaptive response to pathologic stress. We have also shown that the major subtypes, α1A and α1B, both localize to the nucleus in adult cardiac myocytes. Importantly, we have defined a nuclear α1A-ERK survival and an α1A-PKCδ-cTnI inotropic signaling pathway that both originate at the nucleus and are transduced to cytosolic targets, suggesting that the α1A is required for cardiac myocyte survival and contractility. However, less is known about the molecular function of the α1B. In the current study, we examined the role of the α1B-subtype in hypertrophic signaling. First, we identified a bi-partite nuclear localization sequence (NLS) in the carboxy-terminal tail of the receptor. Mutation of the NLS (α1B-NLSmut) disrupted its localization to the nucleus when expressed in adult cardiac myocytes. We then compared hypertrophic signaling of the wild-type α1B- to the mutated receptor by reconstitution in cardiac myocytes lacking endogenous α1B (α1BKO) receptors. Activation of the wild-type receptor by the α1-agonist phenylephrine in α1BKO myocytes restored hypertrophic signaling, as we observed increased phosphorylation of protein kinase C (PKC) isoforms δ and ε, and histone deacetylases (HDAC) 4 and 5. We also observed increased expression of the hypertrophic gene marker, atrial natriuretic factor (ANF). Expression of the α1B-NLSmut failed to activate hypertrophic signaling in α1BKO cardiac myocytes despite phenylephrine stimulation. Together, our data show that nuclear localization of the α1B-subtype is required for hypertrophic signaling and overall further suggest that α1-adrenergic receptors are functional only at the nucleus in cardiac myocytes.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.109.suppl_1.AP193
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1467838-X
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  • 4
    Online Resource
    Online Resource
    Nuclear Localization of α1A‐Adrenergic Receptors Is Required for Signaling in Cardiac Myocytes: An “Inside‐Out” α1‐AR Signaling Pathway
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Journal of the American Heart Association Vol. 3, No. 2 ( 2014-03-24)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 3, No. 2 ( 2014-03-24)
    Abstract: Recent studies indicate that α1‐adrenergic receptors (α1‐ARs) are cardioprotective by preventing cardiac myocyte death and augmenting contractility in heart failure. Although G‐protein‐coupled receptors are assumed to localize to and signal at the plasma membrane, we previously demonstrated that endogenous α1‐ARs localize to the nuclei in adult cardiac myocytes. However, the functional consequence of this nuclear localization remains unclear. Here, we attempted to reconcile nuclear localization of α1‐ARs with their physiologic function by examining α1‐AR‐induced contractility in adult cardiac myocytes. Methods and Results By measuring shortening in unloaded, cultured adult cardiac myocytes, we found that the α1A‐subtype regulated contractility through phosphorylation of cardiac troponin I (cTnI) at the protein kinase C (PKC) site, threonine 144. Reconstitution of an α1A‐subtype nuclear localization mutant in cardiac myocytes lacking α1‐ARs failed to rescue nuclear α1A‐mediated phosphorylation of cTnI and myocyte contractility. Leptomycin B, the nuclear export inhibitor, also blocked α1A‐mediated phosphorylation of cTnI. These data indicate that α1‐AR signaling originates in the nucleus. Consistent with these observations, we localized the α1A‐subtype to the inner nuclear membrane, identified PKCα, δ, and ε in the nucleus, and found that α1‐ARs activate PKCδ in nuclei isolated from adult cardiac myocytes. Finally, we found that a PKCδ nuclear localization mutant blunted α1‐induced phosphorylation of cTnI. Conclusions Together, our data identify a novel, “inside‐out” nuclear α1A‐subtype/PKCδ/cTnI‐signaling pathway that regulates contractile function in adult cardiac myocytes. Importantly, these data help resolve the discrepancy between nuclear localization of α1‐ARs and α1‐AR‐mediated physiologic function.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.113.000145
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 2653953-6
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  • 5
    Online Resource
    Online Resource
    GATA4 is a survival factor in adult cardiac myocytes but is not required for α1A-adrenergic receptor survival signaling
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 295, No. 2 ( 2008-08), p. H699-H707
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 295, No. 2 ( 2008-08), p. H699-H707
    Abstract: Recently, we defined an α1A-adrenergic receptor-ERK (α1A-AR-ERK) survival signaling pathway in adult cardiac myocytes. Previous studies in neonatal cardiac myocytes indicated that the cardiac-specific transcription factor GATA4 is a downstream mediator of α1-ERK signaling and that phosphorylation of GATA4 by ERK increases DNA binding and transcriptional activity. Therefore, we examined GATA4 as a potential downstream effector of α1A-ERK survival signaling in adult cardiac myocytes. We measured norepinephrine (NE)-induced cell death in cultured cardiac myocytes lacking α1-ARs (cultured from α1A/B-AR double-knockout mice, α1ABKO mice) that are susceptible to cell death induced by several proapoptotic stimuli, including NE. Our results show that overexpression of GATA4 is sufficient to protect α1ABKO cardiac myocytes from NE-induced cell death. However, we found that the α1A-subtype did not induce phosphorylation or increase the activity of GATA4 in adult mouse cardiac myocytes in culture or in vivo. Furthermore, we examined the effect of siRNA-mediated knockdown of GATA4 on α1A-survival signaling. In α1B-knockout cardiac myocytes, which express only the α1A-subtype and are protected from NE-induced cell death, GATA4 knockdown did not reverse α1A-survival signaling in response to NE. In summary, we found that GATA4 acted as a survival factor by preventing cell death in α1ABKO cardiac myocytes, but GATA4 was not activated by α1-AR stimulation and was not required for α1A-survival signaling in adult cardiac myocytes. This also identifies an important mechanistic difference in α1-signaling between adult and neonatal cardiac myocytes.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.01204.2007
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Signaling through Free Fatty Acid Receptor 4 Attenuates Cardiometabolic Disease
    American Physiological Society ; 2022
    In:  Physiology Vol. 37, No. 6 ( 2022-11-01), p. 311-322
    Details
    In: Physiology, American Physiological Society, Vol. 37, No. 6 ( 2022-11-01), p. 311-322
    Abstract: A surge in the prevalence of obesity and metabolic syndrome, which promote systemic inflammation, underlies an increase in cardiometabolic disease. Free fatty acid receptor 4 is a nutrient sensor for long-chain fatty acids, like ω3-polyunsaturated fatty acids (ω3-PUFAs), that attenuates metabolic disease and resolves inflammation. Clinical trials indicate ω3-PUFAs are cardioprotective, and this review discusses the mechanistic links between ω3-PUFAs, free fatty acid receptor 4, and attenuation of cardiometabolic disease.
    Type of Medium: Online Resource
    ISSN: 1548-9213 , 1548-9221
    URL: Article
    DOI: 10.1152/physiol.00007.2022
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 3115360-4
    detail.hit.zdb_id: 2005759-3
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Bimolecular modeling and simulation of antagonist binding to the alpha‐1A adrenergic receptor
    Wiley ; 2019
    In:  The FASEB Journal Vol. 33, No. S1 ( 2019-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 33, No. S1 ( 2019-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v33.S1
    DOI: 10.1096/fasebj.2019.33.1_supplement.668.4
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Data_Sheet_1.docx
    Frontiers Media SA ; 2022
    In:  Frontiers in Molecular Neuroscience Vol. 15 ( 2022-10-19)
    Details
    In: Frontiers in Molecular Neuroscience, Frontiers Media SA, Vol. 15 ( 2022-10-19)
    Abstract: The natriuretic peptide receptors NPR1 and NPR2, also known as guanylyl cyclase A and guanylyl cyclase B, have critical functions in many signaling pathways, but much remains unknown about their localization and function in vivo . To facilitate studies of these proteins, we developed genetically modified mouse lines in which endogenous NPR1 and NPR2 were tagged with the HA epitope. To investigate the role of phosphorylation in regulating NPR1 and NPR2 guanylyl cyclase activity, we developed mouse lines in which regulatory serines and threonines were substituted with glutamates, to mimic the negative charge of the phosphorylated forms (NPR1-8E and NPR2-7E). Here we describe the generation and applications of these mice. We show that the HA-NPR1 and HA-NPR2 mice can be used to characterize the relative expression levels of these proteins in different tissues. We describe studies using the NPR2-7E mice that indicate that dephosphorylation of NPR2 transduces signaling pathways in ovary and bone, and studies using the NPR1-8E mice that indicate that the phosphorylation state of NPR1 is a regulator of heart, testis, and adrenal function.
    Type of Medium: Online Resource
    ISSN: 1662-5099
    URL: Article
    URL: Article
    DOI: 10.3389/fnmol.2022.1007026
    DOI: 10.3389/fnmol.2022.1007026.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2452967-9
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  • 9
    Online Resource
    Online Resource
    An association between gene expression and better survival in female mice following myocardial infarction
    Elsevier BV ; 2010
    In:  Journal of Molecular and Cellular Cardiology Vol. 49, No. 5 ( 2010-11), p. 801-811
    Details
    In: Journal of Molecular and Cellular Cardiology, Elsevier BV, Vol. 49, No. 5 ( 2010-11), p. 801-811
    Type of Medium: Online Resource
    ISSN: 0022-2828
    URL: Article
    DOI: 10.1016/j.yjmcc.2010.08.002
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 1469767-1
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  • 10
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    Online Resource
    Atrial Myopathy Quantified by Speckle-Tracking Echocardiography in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Circulation: Cardiovascular Imaging
    Details
    In: Circulation: Cardiovascular Imaging, Ovid Technologies (Wolters Kluwer Health)
    Abstract: Emerging evidence suggests that atrial myopathy may be the underlying pathophysiology that explains adverse cardiovascular outcomes in heart failure (HF) and atrial fibrillation. Lower left atrial (LA) function (strain) is a key biomarker of atrial myopathy, but murine LA strain has not been described, thus limiting translational investigation. Therefore, the objective of this study was to characterize LA function by speckle-tracking echocardiography in mouse models of atrial myopathy. METHODS: We used 3 models of atrial myopathy in wild-type male and female C57Bl6/J mice: (1) aged 16 to 17 months, (2) Ang II (angiotensin II) infusion, and (3) high-fat diet+Nω-nitro- L -arginine methyl ester (HF with preserved ejection fraction, HFpEF). LA reservoir, conduit, and contractile strain were measured using speckle-tracking echocardiography from a modified parasternal long-axis window. Left ventricular systolic and diastolic function, and global longitudinal strain were also measured. Transesophageal rapid atrial pacing was used to induce atrial fibrillation. RESULTS: LA reservoir, conduit, and contractile strain were significantly reduced in aged, Ang II and HFpEF mice compared with young controls. There were no sex-based interactions. Left ventricular diastolic function and global longitudinal strain were lower in aged, Ang II and HFpEF, but left ventricular ejection fraction was unchanged. Atrial fibrillation inducibility was low in young mice (5%), moderately higher in aged mice (20%), and high in Ang II (75%) and HFpEF (83%) mice. CONCLUSIONS: Using speckle-tracking echocardiography, we observed reduced LA function in established mouse models of atrial myopathy with concurrent atrial fibrillation inducibility, thus providing the field with a timely and clinically relevant platform for understanding the pathophysiology and discovery of novel treatment targets for atrial myopathy.
    Type of Medium: Online Resource
    ISSN: 1941-9651 , 1942-0080
    URL: Article
    DOI: 10.1161/CIRCIMAGING.123.015735
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2440475-5
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