Downregulation of Metabolic Gene Expression in Failing Human Heart before and after Mechanical Unloading

Razeghi, Peter
Young, Martin E.
Ying, Jun
Depre, Christophe
Uray, Ivan P.
Kolesar, June
Shipley, Gregory L.
Moravec, Christine S.
Davies, Peter J.A.
Frazier, O. H.
Taegtmeyer, Heinrich

^aDivision of Cardiology and
^bDepartment of Integrative Biology, University of Texas-Houston Medical School, Houston,
^cSt-Luke's Episcopal Hospital and Texas Heart Institute, Houston, Tex., and
^dCenter for Anesthesiology Research, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Accepted after revision: April 13, 2002

Received: January 13, 2002

Heinrich Taegtmeyer, MD

Department of Internal Medicine, Division of Cardiology

University of Texas Houston-Medical School

6431 Fannin, MSB 1.246, Houston, TX 77030 (USA)

Tel. +1 713 500 6567, Fax +1 713 500 6556, E-Mail [email protected]

Cardiology 97(4):p 203-209, 2002. | DOI: 10.1159/000063122

Abstract

Background:

We have previously shown that several metabolic genes are downregulated in the failing human heart. We now tested the hypothesis that mechanical unloading might reverse this process.

Methods:

Clinical data and myocardial tissue were collected from 14 failing hearts paired for the time of implantation and explantation of a left ventricular assist device (LVAD) and compared to 10 non-failing hearts. Transcript levels for key regulators of energy metabolism and for atrial natriuretic factor (ANF) were measured by real-time quantitative RT-PCR.

Results:

The expression of the glucose transporter 1 and 4 (GLUT1, GLUT4), muscle carnitine palmitoyl transferase-1 (mCPT-1), and uncoupling protein 3 (UCP3) were downregulated by up to 80% in the failing heart. Although LVAD treatment improved clinical markers of heart failure (decrease of left ventricular diastolic dimension and normalization of serum sodium), only UCP3 expression reversed to non-failing transcript levels following mechanical unloading.

Conclusions:

LVAD treatment only partially reverses depressed metabolic gene expression in the failing human heart. Reversal of depressed UCP3 expression may be an important mechanism for reducing the formation of oxygen-derived free radicals. Further studies are necessary to define the effects of mechanical unloading on post-transcriptional mechanisms.