Modulation of Ventricular Function Through Gene Transfer in Vivo

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1998 Jun 6

PMID 9560262

Citations 83

Authors

R J Hajjar

U Schmidt

T Matsui

J L Guerrero

K H Lee

J K Gwathmey

G W Dec

M J Semigran

A Rosenzweig

Affiliations

Soon will be listed here.

Abstract

We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). By using this approach, rat hearts were transduced in vivo with 5 x 10(9) pfu of recombinant adenoviral vectors carrying cDNA for either PL, beta-galactosidase (beta-gal), or modified green fluorescent protein (EGFP). Western blot analysis of ventricles obtained from rats transduced by Ad.PL showed a 2.8-fold increase in PL compared with hearts transduced by Ad.betagal. Two days after infection, rat hearts transduced with Ad.PL had lower peak left ventricular pressure (58.3 +/- 12.9 mmHg, n = 8) compared with uninfected hearts (92.5 +/- 3.5 mmHg, n = 6) or hearts infected with Ad.betagal (92.6 +/- 5.9 mmHg, n = 6). Both peak rate of pressure rise and pressure fall (+3, 210 +/- 298 mmHg/s, -2, 117 +/- 178 mmHg/s, n = 8) were decreased in hearts overexpressing PL compared with uninfected hearts (+5, 225 +/- 136 mmHg/s, -3, 805 +/- 97 mmHg/s, n = 6) or hearts infected with Ad.betagal (+5, 108 +/- 167 mmHg/s, -3, 765 +/- 121 mmHg/s, n = 6). The time constant of left ventricular relaxation increased significantly in hearts overexpressing PL (33.4 +/- 3.2 ms, n = 8) compared with uninfected hearts (18.5 +/- 1.0 ms, n = 6) or hearts infected with Ad.betagal (20.8 +/- 2.1 ms, n = 6). These differences in ventricular function were maintained 7 days after infection. These studies open the prospect of using somatic gene transfer to modulate overall cardiac function in vivo for either experimental or therapeutic applications.

Citing Articles

AAV delivery strategy with mechanical support for safe and efficacious cardiac gene transfer in swine.

Mazurek R, Tharakan S, Mavropoulos S, Singleton D, Bikou O, Sakata T Nat Commun. 2024; 15(1):10450.

PMID: 39617804 PMC: 11609281. DOI: 10.1038/s41467-024-54635-x.

Stress-enhanced cardiac lncRNA Morrbid protects hearts from acute myocardial infarction.

Yu Y, Yang H, Li Q, Ding N, Gao J, Qiao G JCI Insight. 2023; 8(16).

PMID: 37432746 PMC: 10543728. DOI: 10.1172/jci.insight.165568.

Progress in Clinical Gene Therapy for Cardiac Disorders.

Romeo F, Mavropoulos S, Ishikawa K Mol Diagn Ther. 2023; 27(2):179-191.

PMID: 36641770 PMC: 10023344. DOI: 10.1007/s40291-022-00632-z.

New N-aryl-N-alkyl-thiophene-2-carboxamide compound enhances intracellular Ca dynamics by increasing SERCA2a Ca pumping.

Nikolaienko R, Bovo E, Yuen S, Treinen L, Berg K, Aldrich C Biophys J. 2022; 122(2):386-396.

PMID: 36463408 PMC: 9892616. DOI: 10.1016/j.bpj.2022.12.002.

Cas9/AAV9-Mediated Somatic Mutagenesis Uncovered the Cell-Autonomous Role of Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 in Murine Cardiomyocyte Maturation.

Lin J, Chen Z, Yang L, Liu L, Yue P, Sun Y Front Cell Dev Biol. 2022; 10:864516.

PMID: 35433671 PMC: 9012521. DOI: 10.3389/fcell.2022.864516.

References

HARIGAYA S, Schwartz A . Rate of calcium binding and uptake in normal animal and failing human cardiac muscle. Membrane vesicles (relaxing system) and mitochondria. Circ Res. 1969; 25(6):781-94. DOI: 10.1161/01.res.25.6.781. View

Giordano F, He H, McDonough P, Meyer M, Sayen M, Dillmann W . Adenovirus-mediated gene transfer reconstitutes depressed sarcoplasmic reticulum Ca2+-ATPase levels and shortens prolonged cardiac myocyte Ca2+ transients. Circulation. 1997; 96(2):400-3. DOI: 10.1161/01.cir.96.2.400. View

Karczewski P, Bartel S, Krause E . Differential sensitivity to isoprenaline of troponin I and phospholamban phosphorylation in isolated rat hearts. Biochem J. 1990; 266(1):115-22. PMC: 1131103. DOI: 10.1042/bj2660115. View

Gwathmey J, Morgan J . Sarcoplasmic reticulum calcium mobilization in right ventricular pressure-overload hypertrophy in the ferret: relationships to diastolic dysfunction and a negative treppe. Pflugers Arch. 1993; 422(6):599-608. DOI: 10.1007/BF00374008. View

Gwathmey J, Bentivegna L, Ransil B, Grossman W, Morgan J . Relationship of abnormal intracellular calcium mobilisation to myocyte hypertrophy in human ventricular myocardium. Cardiovasc Res. 1993; 27(2):199-203. DOI: 10.1093/cvr/27.2.199. View

Barry W, Bridge J . Intracellular calcium homeostasis in cardiac myocytes. Circulation. 1993; 87(6):1806-15. DOI: 10.1161/01.cir.87.6.1806. View

Kirshenbaum L, Maclellan W, Mazur W, French B, Schneider M . Highly efficient gene transfer into adult ventricular myocytes by recombinant adenovirus. J Clin Invest. 1993; 92(1):381-7. PMC: 293622. DOI: 10.1172/JCI116577. View

Guzman R, Lemarchand P, Crystal R, Epstein S, Finkel T . Efficient gene transfer into myocardium by direct injection of adenovirus vectors. Circ Res. 1993; 73(6):1202-7. DOI: 10.1161/01.res.73.6.1202. View

Alvira M, Rivera J, Buttrick P, Wittenberg B, Cipriani L, Leinwand L . Quantitative determination of adenovirus-mediated gene delivery to rat cardiac myocytes in vitro and in vivo. Proc Natl Acad Sci U S A. 1993; 90(24):11498-502. PMC: 48011. DOI: 10.1073/pnas.90.24.11498. View

10.

Arai M, Matsui H, Periasamy M . Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ Res. 1994; 74(4):555-64. DOI: 10.1161/01.res.74.4.555. View

11.

Luo W, GRUPP I, Harrer J, Ponniah S, GRUPP G, Duffy J . Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res. 1994; 75(3):401-9. DOI: 10.1161/01.res.75.3.401. View

12.

French B, Mazur W, Geske R, Bolli R . Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation. 1994; 90(5):2414-24. DOI: 10.1161/01.cir.90.5.2414. View

13.

Barr E, Carroll J, Kalynych A, Tripathy S, Kozarsky K, Wilson J . Efficient catheter-mediated gene transfer into the heart using replication-defective adenovirus. Gene Ther. 1994; 1(1):51-8. View

14.

Elfenbein D, Alvira M, Buttrick P, Leinwand L . The impact of developmental stage, route of administration and the immune system on adenovirus-mediated gene transfer. Gene Ther. 1994; 1(6):395-402. View

15.

OBrien P, Gwathmey J . Myocardial Ca(2+)- and ATP-cycling imbalances in end-stage dilated and ischemic cardiomyopathies. Cardiovasc Res. 1995; 30(3):394-404. DOI: 10.1016/s0008-6363(95)00059-3. View

16.

Dong G, Schulick A, DeYoung M, Dichek D . Identification of a cis-acting sequence in the human plasminogen activator inhibitor type-1 gene that mediates transforming growth factor-beta1 responsiveness in endothelium in vivo. J Biol Chem. 1996; 271(47):29969-77. DOI: 10.1074/jbc.271.47.29969. View

17.

Koss K, Kranias E . Phospholamban: a prominent regulator of myocardial contractility. Circ Res. 1996; 79(6):1059-63. DOI: 10.1161/01.res.79.6.1059. View

18.

Chu G, Luo W, Slack J, Tilgmann C, Sweet W, Spindler M . Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts. Circ Res. 1996; 79(6):1064-76. DOI: 10.1161/01.res.79.6.1064. View

19.

Hajjar R, Kang J, Gwathmey J, Rosenzweig A . Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation. 1997; 95(2):423-9. DOI: 10.1161/01.cir.95.2.423. View

20.

Lalli J, Harrer J, Luo W, Kranias E, Paul R . Targeted ablation of the phospholamban gene is associated with a marked decrease in sensitivity in aortic smooth muscle. Circ Res. 1997; 80(4):506-13. DOI: 10.1161/01.res.80.4.506. View