Objective: The secretory glycoprotein renin can be deleterious to the heart, promoting the progression of cardiac failure through inflammation, apoptotic and necrotic cell death. Interestingly the heart itself expresses a non- secretory cytosolic renin variant. Expression of this transcript is upregulated after cardiac infarction in vivo and reduces infarct size in hearts from transgenic rats overexpressing cytosolic renin after ex vivo ischemia. Aim of the present study was to test the hypothesis that overexpression of cytosolic renin protects cardiac cells under ischemia-associated conditions. Methods: pIRES vector- or exon(2-9)renin- transfected cardiac H9c2 cells were exposed to rotenone (5 mM), glucose depletion for 24 h or 400 mM H₂O₂ for 30 min. ATP content, necrosis rate (LDH release/LDH content) and apoptosis Caspase+ cells) were determined. Results: Rotenone decreased ATP content in pIRES cells (479±35 to 393±32x10³ RLU, p<0.05) but not in exon(2-9)renin+ cells (321±43 to 351±45x10³ RLU). Necrotis of pIRES cells increased from 11.5±1.4 to 21.7±2.3% and apoptosis from 10.2±1.1 to 22.8±1.3% (p<0.05). In exon(2-9)renin+ cells the increase of necrosis was less pronounced (9.9±1.6 to 15.4±1.0%, p<0.05) and the apoptosis rate did not change. Glucose depletion decreased ATP content (367±31x10³ RLU, p<0.05) and enhanced necrosis in pIRES cells (22.3±3.3%, p<0.01) but not in exon(2-9) renin+ cells. Exposure of cells to H₂O₂ significantly increased necrosis to 82.0±7.8% in pIRES but only to 60.7±9.7% in exon(2-9)renin+ cells. The number of Caspase+ cells increased to 64.9±3.7% in pIRES and only to 42.0±6.9% in exon(2-9)renin+ cells. Conclusions: Cytosolic exon(2-9)renin protects cardiac cells from both necrotic and apoptotic cell death induced by ischemia-associated factors. These effects may be due to the maintenance of ATP content.