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  • 1
    Online Resource
    Online Resource
    Endogenous regulation of cardiovascular function by apelin-APJ
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 297, No. 5 ( 2009-11), p. H1904-H1913
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 297, No. 5 ( 2009-11), p. H1904-H1913
    Abstract: Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00686.2009
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Cardiac pressure overload hypertrophy is differentially regulated by β-adrenergic receptor subtypes
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 301, No. 4 ( 2011-10), p. H1461-H1470
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 301, No. 4 ( 2011-10), p. H1461-H1470
    Abstract: In isolated myocytes, hypertrophy induced by norepinephrine is mediated via α 1 -adrenergic receptors (ARs) and not β-ARs. However, mice with deletions of both major cardiac α 1 -ARs still develop hypertrophy in response to pressure overload. Our purpose was to better define the role of β-AR subtypes in regulating cardiac hypertrophy in vivo, important given the widespread clinical use of β-AR antagonists and the likelihood that patients treated with these agents could develop conditions of further afterload stress. Mice with deletions of β 1 , β 2 , or both β 1 - and β 2 -ARs were subjected to transverse aortic constriction (TAC). After 3 wk, β 1 −/− showed a 21% increase in heart to body weight vs. sham controls, similar to wild type, whereas β 2 −/− developed exaggerated (49% increase) hypertrophy. Only when both β-ARs were ablated (β 1 β 2 −/− ) was hypertrophy totally abolished. Cardiac function was preserved in all genotypes. Several known inhibitors of cardiac hypertrophy (FK506 binding protein 5, thioredoxin interacting protein, and S100A9) were upregulated in β 1 β 2 −/− compared with the other genotypes, whereas transforming growth factor-β 2 , a positive mediator of hypertrophy was upregulated in all genotypes except the β 1 β 2 −/− . In contrast to recent reports suggesting that angiogenesis plays a critical role in regulating cardiac hypertrophy-induced heart failure, we found no evidence that angiogenesis or its regulators (VEGF, Hif1α, and p53) play a role in compensated cardiac hypertrophy. Pressure overload hypertrophy in vivo is dependent on a coordination of signaling through both β 1 - and β 2 -ARs, mediated through several key cardiac remodeling pathways. Angiogenesis is not a prerequisite for compensated cardiac hypertrophy.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00453.2010
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Physiologic and molecular characterization of a murine model of right ventricular volume overload
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 304, No. 10 ( 2013-05-15), p. H1314-H1327
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 304, No. 10 ( 2013-05-15), p. H1314-H1327
    Abstract: Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization, and exercise testing were performed at 1, 3, and 6 mo and compared with sham controls. RNA from the RV free wall was hybridized to Agilent whole genome oligonucleotide microarrays. Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 mo followed by normalization at 3 and 6 mo (39 ± 2, 44 ± 2, and 41 ± 2 vs. 46 ± 3% in sham), early reversal of early and late diastolic filling velocities (E/A ratio) followed by pseudonormalization (0.87 ± 0.08, 0.82 ± 0.08, and 0.96 ± 0.08 vs. 1.04 ± 0.03; P 〈 0.05), elevated end-diastolic pressure (7.6 ± 0.7, 6.9 ± 0.8, and 7 ± 0.5 vs. 2.7 ± 0.2 mmHg; P 〈 0.05), and decreased exercise duration (26 ± 0.4, 26 ± 1, and 22 ± 1.3 vs. 30 ± 1.1 min; P 〈 0.05). Subendocardial RV fibrosis was evident by 1 mo. At 1 mo, 372 genes were significantly downregulated. Mitochondrial pathways and G protein-coupled receptor signaling were the most represented categories. At 3 mo, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, transforming growth factor-β 1 (TGF-β 1 ), p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-β signaling, ECM remodeling, and apoptosis.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00776.2012
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 295, No. 3 ( 2008-09), p. H1351-H1368
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 295, No. 3 ( 2008-09), p. H1351-H1368
    Abstract: Right ventricular (RV) dysfunction is a common long-term complication in patients after the repair of congenital heart disease. Previous investigators have examined the cellular and molecular mechanisms of left ventricular (LV) remodeling, but little is known about the stressed RV. Our purpose was to provide a detailed physiological characterization of a model of RV hypertrophy and failure, including RV-LV interaction, and to compare gene alterations between afterloaded RV versus LV. Pulmonary artery constriction was performed in 86 mice. Mice with mild and moderate pulmonary stenosis (PS) developed stable hypertrophy without decompensation. Mice with severe PS developed edema, decreased RV function, and high mortality. Tissue Doppler imaging demonstrated septal dyssynchrony and deleterious RV-LV interaction in the severe PS group. Microarray analysis showed 196 genes with increased expression and 1,114 with decreased expression. Several transcripts were differentially increased in the afterloaded RV but not in the afterloaded LV, including clusterin, neuroblastoma suppression of tumorigenicity 1, Dkk3, Sfrp2, formin binding protein, annexin A7, and lysyl oxidase. We have characterized a murine model of RV hypertrophy and failure, providing a platform for studying the physiological and molecular events of RV remodeling. Although the molecular responses of the RV and LV to afterload stress are mostly concordant, there are several key differences, which may represent targets for RV failure-specific therapy.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.91526.2007
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 305, No. 4 ( 2013-08-15), p. H551-H562
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 305, No. 4 ( 2013-08-15), p. H551-H562
    Abstract: Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28α subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight), RV dilation with septal shift, RV dysfunction, and clinical RVF. Proteasomal function (26S β 5 chymotrypsin-like activity) was decreased 26% ( P 〈 0.05). Protein expression of 19S subunit Rpt5 ( P 〈 0.05), UCHL1 deubiquitinase ( P 〈 0.0001), and Smurf1 E3 ubiquitin ligase ( P 〈 0.01) were increased, as were polyubiquitinated proteins ( P 〈 0.05) and free-ubiquitins ( P = 0.05). Pro-apoptotic Bax was increased ( P 〈 0.0001), whereas anti-apoptotic Bcl-2 decreased ( P 〈 0.05), resulting in a sixfold increase in the Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiac-specific proteasome overexpression partially improved survival. Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF, suggesting that UPS dysfunction contributes to RVF.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00771.2012
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 24 ( 2021-06-15)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 24 ( 2021-06-15)
    Abstract: Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, associated with over 1,000 mutations, many in β-cardiac myosin (MYH7). Molecular studies of myosin with different HCM mutations have revealed a diversity of effects on ATPase and load-sensitive rate of detachment from actin. It has been difficult to predict how such diverse molecular effects combine to influence forces at the cellular level and further influence cellular phenotypes. This study focused on the P710R mutation that dramatically decreased in vitro motility velocity and actin-activated ATPase, in contrast to other MYH7 mutations. Optical trap measurements of single myosin molecules revealed that this mutation reduced the step size of the myosin motor and the load sensitivity of the actin detachment rate. Conversely, this mutation destabilized the super relaxed state in longer, two-headed myosin constructs, freeing more heads to generate force. Micropatterned human induced pluripotent derived stem cell (hiPSC)–cardiomyocytes CRISPR-edited with the P710R mutation produced significantly increased force (measured by traction force microscopy) compared with isogenic control cells. The P710R mutation also caused cardiomyocyte hypertrophy and cytoskeletal remodeling as measured by immunostaining and electron microscopy. Cellular hypertrophy was prevented in the P710R cells by inhibition of ERK or Akt. Finally, we used a computational model that integrated the measured molecular changes to predict the measured traction forces. These results confirm a key role for regulation of the super relaxed state in driving hypercontractility in HCM with the P710R mutation and demonstrate the value of a multiscale approach in revealing key mechanisms of disease.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2025030118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Epicardial FSTL1 reconstitution regenerates the adult mammalian heart
    Springer Science and Business Media LLC ; 2015
    In:  Nature Vol. 525, No. 7570 ( 2015-9), p. 479-485
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 525, No. 7570 ( 2015-9), p. 479-485
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature15372
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 8
    Online Resource
    Online Resource
    Load-dependent effects of apelin on murine cardiomyocytes
    Elsevier BV ; 2017
    In:  Progress in Biophysics and Molecular Biology Vol. 130 ( 2017-11), p. 333-343
    Details
    In: Progress in Biophysics and Molecular Biology, Elsevier BV, Vol. 130 ( 2017-11), p. 333-343
    Type of Medium: Online Resource
    ISSN: 0079-6107
    URL: Article
    DOI: 10.1016/j.pbiomolbio.2017.09.013
    RVK:
    WD 1002
    RVK:
    WA 1000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 1498578-0
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes
    American Physiological Society ; 2005
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 289, No. 6 ( 2005-12), p. H2441-H2449
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 289, No. 6 ( 2005-12), p. H2441-H2449
    Abstract: Recent data suggest that β-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of β1- vs. β2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to β1, β2, and β1/β2 knockout ( −/− ) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and β1 −/− mice showed no acute cardiovascular effects, whereas β2 −/− mice all died within 30 min. The additional deletion of the β1-receptor (β1/β2 −/− ) totally rescued this toxicity. β2 −/− mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued β2 −/− mice from this acute toxicity. The enhanced toxicity in β2 −/− mice was also recapitulated in wild-type mice with the β2-selective antagonist ICI-118,551, although the rescue effect of the β1-deletion was not recapitulated using the β1-selective antagonist metoprolol or the nonselective β-antagonist propranolol. These data suggest that β2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas β1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate β-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these β-adrenergic receptor subtypes in vivo.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00005.2005
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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