Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program.
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 AT(1) receptor blocker irbesartan markedly blunted stretch-mediated GDF15 and Hmox1 upregulation, suggesting that the angiotensin receptor transduces 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.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D016678:Genome; D006352:Heart Ventricles; D006984:Hypertrophy / Q000139:chemically induced / Q000209:etiology; D046228:Microarray Analysis; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical
D000316:Adrenergic alpha-Agonists; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D010656:Phenylephrine