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  • 1
    Online Resource
    Online Resource
    Decreased Efficiency of Adenovirus-Mediated Gene Transfer in Aging Cardiomyocytes
    Ovid Technologies (Wolters Kluwer Health) ; 2003
    In:  Circulation Vol. 107, No. 8 ( 2003-03-04), p. 1170-1175
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 107, No. 8 ( 2003-03-04), p. 1170-1175
    Abstract: Background— Aging is an independent risk factor for the development of cardiovascular disease. Clinical application of myocardial gene transfer may be best suited in the elderly. In vivo gene transfer by adenovirus is less efficient in aging myocardium. Methods and Results— When infected with adenovirus containing β-galactosidase (β-gal) and green fluorescent protein (GFP) driven by cytomegalovirus promoters in vitro, aging rat cardiac myocytes exhibit significantly lower infectivity and delayed transgene expression compared with adult controls. Abnormalities of viral internalization may be one mechanism accounting for this difference. To investigate this, we studied expression levels of the coxsackievirus and adenovirus receptor (CAR) as well as other potential integrins involved in the internalization of adenoviruses. CAR expression tended to be upregulated whereas among potential integrins, α 3 β 1 was downregulated in aging cardiac myocytes. Blocking the β 1 component of α 3 β 1 further decreased infectivity, suggesting that the interaction between the penton base of the adenovirus and β 1 maybe a crucial component of the viral entry mechanism. Conclusions— These results suggest that it is integrin-stimulated internalization rather than the adenovirus-CAR interaction that plays a vital role in adenoviral entry. The downregulation of integrins observed in senescent cells may be a key mechanism accounting for the decrease in viral infectivity seen in these cells. These findings have implications for the gene therapy treatment of myocardial failure in the elderly.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000051467.31874.29
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2003
    detail.hit.zdb_id: 1466401-X
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  • 2
    Online Resource
    Online Resource
    In Vivo Cardiac Gene Transfer of Kv4.3 Abrogates the Hypertrophic Response in Rats After Aortic Stenosis
    Ovid Technologies (Wolters Kluwer Health) ; 2004
    In:  Circulation Vol. 110, No. 22 ( 2004-11-30), p. 3435-3443
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 110, No. 22 ( 2004-11-30), p. 3435-3443
    Abstract: Background— Prolongation of the action potential duration (APD) and decreased transient outward K + current ( I to ) have been consistently observed in cardiac hypertrophy. The relation between electrical remodeling and cardiac hypertrophy in vivo is unknown. Methods and Results— We studied rat hearts subjected to pressure overload by surgical ascending aortic stenosis (AS) and simultaneously infected these hearts with an adenovirus carrying either the Kv4.3 gene ( Ad.Kv4.3 ) or the β-galactosidase gene ( Ad.β-gal ). I to density was reduced and APD 50 was prolonged ( P 〈 0.05) in AS rats compared with sham rats. Kv4.2 and Kv4.3 expressions were decreased by 58% and 51%, respectively ( P 〈 0.05). AS rats infected with Ad.β-gal developed cardiac hypertrophy compared with sham rats, as assessed by cellular capacitance and heart weight–body weight ratio. Associated with the development of cardiac hypertrophy, the expression of calcineurin and its downstream transcription factor nuclear factor of activated T cells (NFAT) c1 was persistently increased by 47% and 36%, respectively ( P 〈 0.05) in AS myocytes infected with Ad.β-gal compared with sham myocytes. In vivo gene transfer of Kv4.3 in AS rats was shown to increase Kv4.3 expression, increase I to density, and shorten APD 50 by 1.6-fold, 5.3-fold, and 3.6-fold, respectively ( P 〈 0.05). Furthermore, AS rats infected with Ad.Kv4.3 showed significant reductions in calcineurin and NFAT expression. ( P 〈 0.05). Conclusions— Downregulation of I to , APD prolongation, and cardiac hypertrophy occur early after AS, and in vivo gene transfer of Kv4.3 can restore these electrical parameters and abrogate the hypertrophic response via the calcineurin pathway.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000148176.33730.3F
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2004
    detail.hit.zdb_id: 1466401-X
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  • 3
    Online Resource
    Online Resource
    Myofilament Calcium Regulation in Human Myocardium
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Circulation Vol. 101, No. 14 ( 2000-04-11), p. 1679-1685
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 101, No. 14 ( 2000-04-11), p. 1679-1685
    Abstract: Background —We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure. Methods and Results —Calcium concentration required for 50% activation and Hill coefficient for fibers from nonfailing and failing human hearts at pH 7.1 were not different. Maximum calcium-activated force (F max ) was also not different. However, at pH 6.8 and 6.9, differences were seen in myofilament calcium activation between nonfailing and failing hearts. At lower pH, failing myocardium was shifted left on the calcium axis compared with nonfailing myocardium, which suggested an increase in myofilament calcium responsiveness. Increased inorganic phosphate concentration decreased maximal force development by 56% in nonfailing and 36% in failing myocardium and shifted the calcium-force relationship by 2.01±0.22 versus 0.86±0.13 μmol/L, respectively ( P 〈 0.05). Addition of cAMP resulted in a 0.56 μmol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 μmol/L shift in failing myocardium. Protein kinase A in the presence of cAMP resulted in a further rightward shift in nonfailing human myocardium but did not further shift the calcium-force relationship in fibers from failing hearts. cGMP also resulted in a greater decrease in myofilament calcium sensitivity in fibers from failing hearts. Conclusions— We propose that changes at the level of the thin myofilaments result in differential responses to changes in the intracellular milieu in nonfailing versus failing myocardium.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.101.14.1679
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1466401-X
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  • 4
    Online Resource
    Online Resource
    Human heart failure: cAMP stimulation of SR Ca 2+ -ATPase activity and phosphorylation level of phospholamban
    American Physiological Society ; 1999
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 277, No. 2 ( 1999-08-01), p. H474-H480
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 277, No. 2 ( 1999-08-01), p. H474-H480
    Abstract: Failing human myocardium has been associated with decreased sarcoplasmic reticulum (SR) Ca 2+ -ATPase activity. There remains controversy as to whether the regulation of SR Ca 2+ -ATPase activity is altered in heart failure or whether decreased SR Ca 2+ -ATPase activity is due to changes in SR Ca 2+ -ATPase or phospholamban expression. We therefore investigated whether alterations in cAMP-dependent phosphorylation of phospholamban may be responsible for the reduced SR Ca 2+ -ATPase activity in human heart failure. Protein levels of phospholamban and SR Ca 2+ -ATPase, detected by Western blot, were unchanged in failing compared with nonfailing human myocardium. There was decreased responsiveness to the direct activation of the SR Ca 2+ -ATPase activity by either cAMP (0.01–100 μmol/l) or protein kinase A (1–30 μg) in failing myocardium. Using the backphosphorylation technique, we observed a decrease of the cAMP-dependent phosphorylation level of phospholamban by 20 ± 2%. It is concluded that the impaired SR function in human end-stage heart failure may be due, in part, to a reduced cAMP-dependent phosphorylation of phospholamban.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.1999.277.2.H474
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1999
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Reversal of Cardiac Dysfunction After Long-Term Expression of SERCA2a by Gene Transfer in a Pre-Clinical Model of Heart Failure
    Elsevier BV ; 2008
    In:  Journal of the American College of Cardiology Vol. 51, No. 11 ( 2008-03), p. 1112-1119
    Details
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 51, No. 11 ( 2008-03), p. 1112-1119
    Type of Medium: Online Resource
    ISSN: 0735-1097
    URL: Article
    DOI: 10.1016/j.jacc.2007.12.014
    RVK:
    XA 17760
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 1468327-1
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  • 6
    Online Resource
    Online Resource
    Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 15 ( 2004-04-13), p. 5622-5627
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 15 ( 2004-04-13), p. 5622-5627
    Abstract: Abnormal intracellular Ca 2+ cycling plays an important role in cardiac dysfunction and ventricular arrhythmias in the setting of heart failure and transient cardiac ischemia followed by reperfusion (I/R). We hypothesized that overexpression of the sarcoplasmic reticulum Ca 2+ ATPase pump (SERCA2a) may improve both contractile dysfunction and ventricular arrhythmias. Continuous ECG recordings were obtained in 46 conscious rats after adenoviral gene transfer of either SERCA2a or the reporter gene β-galactosidase (βgal) or parvalbumin (PV), as early as 48 h before and 48 h after 30 min ligation of the left anterior descending artery by using an implantable telemetry system. Sham-operated animals were used for comparison for hemodynamic measurements, whereas within-animal baseline was used for electrocardiographic and echocardiographic parameters. All episodes of nonsustained ventricular tachycardia (VT) and ventricular fibrillation (VF) were counted, and their durations were summed by telemetry. I/R decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise (+dP/dt) and ventricular pressure fall (–dP/dt). SERCA2a restored regional wall thickening and +dP/dt and –dP/dt to levels seen preoperatively. Regional-wall motion and anterior-wall thickening were improved in the SERCA2a animals, as assessed by echocardiography and piezoelectric crystals. To assess whether these effects are SERCA2a specific, we overexpressed a skeletal-muscle protein, PV, to examine whether Ca 2+ buffering alone can mitigate ventricular arrhythmias. During the first hour after I/R, the rate of nonsustained VT plus VF was 16 ± 5 episodes per h ( n = 6) in the Ad.βgal group, 22 ± 6 in the Ad.PV group, and 4 ± 2( n = 6, P 〈 0.01) in the Ad.SERCA2a group. The decrease in VT plus VF in the Ad.SERCA2a group was consistent throughout the 48 h of monitoring. These results show that improving intracellular Ca 2+ handling by overexpression of SERCA2a restores contractile function and reduces ventricular arrhythmias during I/R.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0305778101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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