A pro-survival effect of polyamine depletion on norepinephrine-mediated apoptosis in cardiac cells: role of signaling enzymes

Abstract

Recent studies report that the primary transmitter of sympathetic nervous system norepinephrine (NE), which is actively produced in failing human heart, is able to induce apoptosis of rat cardiomyocytes. Apoptotic cell death of cardiomyocytes is involved in several cardiovascular diseases including ischemia, hypertrophy and heart failure, therefore representing a potential therapeutic target. The natural occurring polyamines, putrescine, spermidine and spermine, are biogenic amines involved in many cellular processes, including apoptosis. Thus, we have studied the involvement of polyamines in the apoptosis of cardiac cells induced by the treatment with NE. The results indicate that NE caused an early induction of the activity of ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis, followed by a later increase of apoptotic cell death. This effect was prevented in the presence of α-difluoromethylornithine, an irreversible inhibitor of ODC. Moreover, the study of some key signal transduction pathways revealed an involvement of AMP-activated protein kinase, AKT and p38 mitogen-activated protein kinases, in the modulation by polyamines of the response of cardiomyocytes to NE. In fact, polyamine-depleted cells showed an altered activation pattern of these kinases that may contrast apoptosis and appeared to result from a differential effect on the specific phosphatases that dephosphorylate and switch off these signaling proteins. In conclusion, these results indicate that in cardiac cells polyamines are involved in the execution of the death program activated by NE, and suggest that their apoptosis facilitating action is mediated by a network of specific phosphatases and kinases.

Protective Role of Taurine Against Morphine-Induced Neurotoxicity in C6 Cells via Inhibition of Oxidative Stress

“…Previous studies reported that acute taurine co-treatment or pre-treatment prevents ethanol-induced changes in acetylcholinesterase activity and ethanol-induced release of dopamine (Rosemberg et al 2010;Ericson et al 2010). Imbalance of some neurotransmitters, such as dopamine (Radl et al 2011;Aslan et al 2011), norepinephrine (Cetrullo et al 2011;LaJevic et al 2011) could be directly or indirectly related to apoptosis event, which is consistent with the results of western blot results Bcl-2 and caspase-3 in this study.…”

Polyamine Depletion Attenuates Isoproterenol-Induced Hypertrophy and Endoplasmic Reticulum Stress in Cardiomyocytes

“…These results are consistent with recent papers reporting a similar protective effect of DFMO against apoptosis in cardiac cells treated with aldosterone, or when cells were exposed to simulated ischemia conditions [20,21]. A study investigating the effects of polyamine depletion on norepinephrine mediated apoptosis in rat neonatal cardiomyocytes and H 9 C 2 cardiomyoblasts demonstrated that DFMO had a pro-survival effect that was mediated through a specific network of phosphatases and kinases [22]. …”

The Polyamine Pathway as a Potential Target for Vascular Diseases: Focus on Restenosis

“…Some recent studies support a pro-apoptotic effect of polyamines. Among them, a study revealed that cell apoptosis induced by norepinephrine in rat cardiomyocytes is mediated by an early induction of ODC, and that these effects are prevented by DFMO [55]. These authors also revealed that the pro-apoptotic effect of polyamines is mediated by the involvement of AMP-activated protein kinase, AKT and p38 mitogen-activated protein kinases.…”