This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 51/2/309    most recent HYPERTENSIONAHA.107.098046v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Frank, D. Articles by Frey, N. Search for Related Content PubMed PubMed Citation Articles by Frank, D. Articles by Frey, N. Related Collections ACE/Angiotension receptors Gene expression Hypertrophy Physiological and pathological control of gene expression

(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

This article has been cited by other articles:

				L. Lind, L. Wallentin, T. Kempf, H. Tapken, A. Quint, B. Lindahl, S. Olofsson, P. Venge, A. Larsson, J. Hulthe, et al. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study Eur. Heart J., October 1, 2009; 30(19): 2346 - 2353. [Abstract] [Full Text] [PDF]

				X.-Y. Zhu, E. Daghini, A. R. Chade, D. Versari, J. D. Krier, K. B. Textor, A. Lerman, and L. O. Lerman Myocardial microvascular function during acute coronary artery stenosis: effect of hypertension and hypercholesterolaemia Cardiovasc Res, July 15, 2009; 83(2): 371 - 380. [Abstract] [Full Text] [PDF]

				T. Kempf, J.-M. Sinning, A. Quint, C. Bickel, C. Sinning, P. S. Wild, R. Schnabel, E. Lubos, H. J. Rupprecht, T. Munzel, et al. Growth-Differentiation Factor-15 for Risk Stratification in Patients With Stable and Unstable Coronary Heart Disease: Results From the AtheroGene Study Circ Cardiovasc Genet, June 1, 2009; 2(3): 286 - 292. [Abstract] [Full Text] [PDF]

				S. Champetier, A. Bojmehrani, J. Beaudoin, D. Lachance, E. Plante, E. Roussel, J. Couet, and M. Arsenault Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the {beta}-adrenergic and renin-angiotensin systems Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H669 - H677. [Abstract] [Full Text] [PDF]

				N. Nickel, T. Kempf, H. Tapken, J. Tongers, F. Laenger, U. Lehmann, H. Golpon, K. Olsson, M. R. Wilkins, J. S. R. Gibbs, et al. Growth Differentiation Factor-15 in Idiopathic Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., September 1, 2008; 178(5): 534 - 541. [Abstract] [Full Text] [PDF]

				V. G. Barauna, F. C. Magalhaes, J. E. Krieger, and E. M. Oliveira AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R381 - R387. [Abstract] [Full Text] [PDF]