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Melusin is an integrin β1-interacting protein proposed to act as a biomechanical sensor in the heart. We characterized mechanisms and signalling pathways regulating cardiac melusin expression.Infusion of arginine8-vasopressin (AVP) in Sprague-Dawley (SD) rats, spontaneously hypertensive rats (SHR) and double transgenic rats (dTGR) harbouring both human angiotensinogen and renin genes as well as infusion of angiotensin II (Ang II) in SD rats were used. The effect of direct left ventricular (LV) wall stretch was analysed by using isolated perfused rat heart preparation. For the cell culture studies, mouse atrial HL-1 cell line and neonatal rat ventricular myocytes (NRVMs) were used.Left atrial melusin mRNA levels increased already after 30 min of AVP infusion. Ang II caused significant upregulation of left atrial melusin mRNA (2.1-fold at 6 h, P < 0.05) and protein (1.9-fold at 72 h, P < 0.05) levels. In contrast, LV melusin mRNA levels remained unchanged in response to both infusions, as well as to aortic banding-induced pressure overload. Direct LV wall stress or late-stage hypertensive heart disease did not modify LV melusin gene expression either. Interestingly, in atrial HL-1 cells, cyclic stretching increased melusin mRNA levels. Stretching and treatments with hypertrophic agonists increased melusin mRNA and protein levels in NRVMs, endothelin-1 being the most potent. PD98059, an extracellular signal-regulated protein kinase 1/2 inhibitor, markedly attenuated the endothelin-1-induced upregulation of melusin gene expression in NRVMs.Multiple hypertrophic stimuli regulate melusin expression predominately in the atria, which may represent a necessary initial step in early adaptive remodelling processes.