Distinct Gene Expression Patterns in Biomechanically Stretched Cardiomyocytes

Neonatal rat ventricular cardiomyocytes (NRVCMs) were stretched biaxially (112%/24h) or stimulated with phenylephrine (PE, 50 uM), both resulting in a similar degree of hypertrophy. Unstretched NRVCMs served as negative control. Affymetrix microarray analysis revealed 164 genes more than 2.0-fold up- and 21 genes less than 0.5-fold downregulated (p<0.01). Differential expression was confirmed by real-time PCR. Several genes of the “fetal gene program”, i.e. BNP (4.2-fold, all p<0.05) were induced by stretch as well as PE. We also verified the upregulation of known stretch-responsive genes, including HSP70 (20.9x) and c-myc (3.0x). Moreover, we identified genes exclusively induced by stretch, such as the cardioprotective and antihypertrophic cytokine GDF15 (24.8x) and the antihypertrophic factor heme oxygenase 1 (Hmox1, 10.8x; both confirmed on protein level). Of note, neither PE nor endothelin-1 were able to upregulate GDF15 and Hmox1, while angiotensin II significantly induced both genes. Conversely, addition of the AT1 receptor blocker irbesartan markedly blunted stretch-mediated GDF15 and Hmox1 induction, suggesting that the angiotensin II receptor mediates stretch-dependent signals. In conclusion, we report a comprehensive gene expression profile of cardiomyocytes subjected to biomechanical stress in comparison to pharmacologically induced hypertrophy. Our data imply that a stretch-specific gene program exists, that is mediated, at least in part, by angiotensin-II-dependent signalling. Keywords: stress response Three conditions were compared with two replicates each. These are: (1) control, i.e. no treatment; (2) induction by phenylephrine (50 uM); (3) induction by biomechanical stretch (112%/24h)