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(Hypertension. 2008;51:309.)
© 2008 American Heart Association, Inc.

Original Articles

Gene Expression Pattern in Biomechanically Stretched Cardiomyocytes

Evidence for a Stretch-Specific Gene Program

Derk Frank; Christian Kuhn; Benedikt Brors; Christiane Hanselmann; Mark Lüdde; Hugo A. Katus; Norbert Frey

From the Department of Internal Medicine III (D.F., C.K., C.H., M.L., H.A.K., N.F.), University of Heidelberg, and the Division of Intelligent Bioinformatics Systems (B.B.), DKFZ, Heidelberg, Germany.

Correspondence to Norbert Frey, MD, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. E-mail norbert.frey{at}med.uni-heidelberg.de

Biomechanical stress ie, attributable to pressure overload, leads to cardiac hypertrophy and may ultimately cause heart failure. Yet, it is still unclear how mechanical stress is sensed and transduced on the molecular level. To systematically elucidate the underlying signal transduction pathways, we analyzed the gene expression profile of stretched cardiomyocytes on a genome-wide scale in comparison with other inducers of hypertrophy such as pharmacological stimulation. Neonatal rat ventricular cardiomyocytes were either stretched biaxially or stimulated with phenylephrine (PE), both resulting in a similar degree of hypertrophy. Microarray analyses revealed 164 genes >2.0-fold up- and 21 genes <0.5-fold downregulated (P<0.01). Differential expression was confirmed by real-time polymerase chain reaction. Genes of the "fetal gene program" such as BNP were induced by both stretch (4.2x) and PE (2.9x). We also verified upregulation of known stretch-responsive genes, including HSP70 (20.9x) and c-myc (3.0x). Moreover, several genes were found to be preferentially induced by stretch, such as the cardioprotective cytokine GDF15 (24.8x) and heme oxygenase 1 (Hmox1, 10.8x; both confirmed on protein level). Neither PE nor endothelin-1 upregulated GDF15 and Hmox1, whereas angiotensin II significantly induced both genes. Conversely, the AT₁ receptor blocker irbesartan markedly blunted stretch-mediated GDF15 and Hmox1 upregulation, suggesting that the angiotensin receptor tranduces the biomechanical induction of these genes. In conclusion, we report a comprehensive gene expression profile of cardiomyocytes subjected to biomechanical stress in comparison with pharmacologically induced hypertrophy. Our data imply that a stretch-specific gene program exists, which is mediated, at least in part, by angiotensin II–dependent signaling.

Key Words: hypertrophy • gene expression • microarray analysis • stress • mechanical

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