Dec 11, 1999

Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a

Circulation
del MonteFR J Hajjar

Abstract

Failing human myocardium is characterized by abnormal relaxation, a deficient sarcoplasmic reticulum (SR) Ca(2+) uptake, and a negative frequency response, which have all been related to a deficiency in the SR Ca(2+) ATPase (SERCA2a) pump. To test the hypothesis that an increase in SERCA2a could improve contractile function in cardiomyocytes, we overexpressed SERCA2a in human ventricular myocytes from 10 patients with end-stage heart failure and examined intracellular Ca(2+) handling and contractile function. Overexpression of SERCA2a resulted in an increase in both protein expression and pump activity and induced a faster contraction velocity (26.7+/-6.7% versus 16.6+/-2.7% shortening per second, P<0.005) and enhanced relaxation velocity (32. 0+/-10.1% versus 15.1+/-2.4%, P<0.005). Diastolic Ca(2+) was decreased in failing cardiomyocytes overexpressing SERCA2a (270+/-26 versus 347+/-30 nmol/L, P<0.005), whereas systolic Ca(2+) was increased (601+/-38 versus 508+/-25 nmol/L, P<0.05). In addition, the frequency response was normalized in cardiomyocytes overexpressing SERCA2a. These results support the premise that gene-based therapies and targeting of specific pathways in human heart failure may offer a new modality for the trea...Continue Reading

  • References18
  • Citations228

Citations

Mentioned in this Paper

Cardiomyopathy, Familial Idiopathic
Myocardial Contraction
Ca(2+)-Transporting ATPase
Lymphoma, Non-Hodgkin
Calcium
Gene Expression
Kidney Failure, Chronic
Sarcoplasmic Reticulum
Skeletal Myocytes
Genetic Therapy, Somatic

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