Reduction Of Apoptotic Death Research Articles

Anti-apoptotic agents for the treatment of vascular disease

Background: Recognition of the importance of apoptosis in atherosclerosis could lead to the development of new therapeutic strategies aimed at the reduction of apoptotic death. Many of the available therapeutic agents that have been shown to reduce the progression of the disease and the incidence or recurrence of acute coronary syndromes may have been active, at least in part, through reduction in apoptosis. Statins, antioxidants and thiazolidinediones are implicated in the amelioration of endothelial function, regulation of inflammatory status and downregulation of smooth muscle cell proliferation and migration. Objectives: To evaluate the anti-apoptotic properties of current atherosclerosis therapeutics. Methods: A thorough enquiry in MEDLINE, EMBASE, Cochrane and patent databases was carried out for important original and review articles in the field of vascular anti-apoptotic therapies. Results: Statins, antioxidants and other agents with nonspecific anti-apoptotic properties are effective in preventing adverse cardiovascular events. However, more research in the field of targeted anti-apoptotic therapies may revolutionize therapeutic strategies against atherosclerosis.

Cardioprotective effects and modulation of calcium homeostasis by remifentanil in ischemia‐reperfused rat heart

Intracellular Ca2+ overload induced by ischemia-reperfusion alters Ca2+ homeostasis, which plays an important role in myocardial injury. Even though remifentanil is often used in high doses during anesthetic, little is known about cardioprotective effect associated with Ca2+ homeostasis. In the present study, we showed that remifentanil protects against ischemia-reperfusion injury in the rat heart. In remifentanil-treated rat heart, we observed a decrease in the expression of the pro-apoptotic protein Bax, cytochrome c and myocardial infarct size. We also found that remifentanil treatment enhanced expression of the anti-apoptotic protein Bcl-2 and activation of Erk concerned with survival. Further, remifentanil attenuated abnormal changes of genes involving Ca2+-regulatory mechanism against ischemia-reperfusion injury. These results suggest that remifentanil modulates the expression of genes involved in Ca2+ homeostasis, thereby producing cardioprotective effects through a reduction in apoptotic death.

Contribution of Akt and endothelial nitric oxide synthase to diazoxide-induced late preconditioning.

The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels has a significant role in delayed ischemic preconditioning, and nitric oxide (NO) is a well-known trigger for its activation. However, the source of NO remains unknown. Phosphorylation of endothelial NO synthase (eNOS) increases NO production and reduces apoptosis through the Akt signaling pathway. To elucidate the Akt signaling pathway involved in the opening and antiapoptotic effect of mitoKATP channel during delayed pharmacological preconditioning, the mitoKATP channel opener diazoxide (DE, 7 microg/kg i.p.) alone or DE plus Nomega-nitro-L-arginine methyl ester (L-NAME, 30 microg/kg i.v.), an inhibitor of NOS, or wortmannin (WTN, 15 microg/kg i.v.), an inhibitor of phosphatidylinositol 3'-kinase (PI3 kinase), was administered to wild-type (WT) or eNOS(-/-) mice during DE treatment. Twenty-four hours later, hearts were isolated and subjected to 40 min ischemia and 30 min reperfusion (I/R). The effect of DE and other interventions on hemodynamic, terminal dUTP nick-end labeling staining and biochemical changes during I/R was assessed in mouse hearts. Treatment with DE resulted in a 2.2-fold increase in phosphorylation of Akt and a significant increase in eNOS and inducible NOS (iNOS) proteins. Akt is upstream of NOS and the mitoKATP channel as simultaneous pretreatment of WTN with DE abolished phosphorylation of Akt, which was not affected by L-NAME and 5-hydroxydecanoate. In hearts treated with DE, cardiac function was significantly improved after I/R, and apoptosis was also significantly decreased. WTN abolished the antiapoptotic effect of DE. Similarly, S-methylisothiourea, a specific iNOS inhibitor, when given to eNOS(-/-) mice that were pretreated with DE completely abolished the beneficial effects of DE on reduction of apoptotic death. DE was partially effective in eNOS(-/-) mice against the ischemic injury. It is concluded that DE activates Akt through the PI3 kinase signaling pathway and iNOS and eNOS is downstream of Akt.

Dopamine-induced death of PC12 cells is prevented by a substituted tetrahydronaphthalene

The ability of dopamine to induce apoptosis in a variety of cell types, including PC12 cells and neurons, has been well documented. Under non-reducing conditions, dopamine can be oxidized to semi-quinone and quinone species, which have the ability to arylate proteins and lead to the formation of covalent adducts. Potentially, it is the arylation of substrates critical to cell survival and/or the formation of toxic adducts which leads to the death observed after dopamine treatment. We have previously described the ability of a substituted monohydroxy-tetra-hydronaphthalene (DATN) to bind proteins that are susceptible to arylation by dopamine and related catecholamines. As DATN can prevent the covalent incorporation of dopamine into substrate molecules, we hypothesized that this compound could have a protective effect on cells that undergo apoptotic death in response to dopamine exposure. We report here that DATN prevents the dopamine-induced apoptotic death of PC12 cells in a dose-dependent manner. DATN did not prevent the oxidative stress associated with dopamine treatment, as lipid peroxide production was not influenced by DATN treatment. The ability of DATN to prevent dopamine-induced cell death was selective for this insult, as this compound did not influence the death of PC12 cells induced by hydrogen peroxide (H 2O 2). Consistent with this finding, DATN did not alter lipid peroxidation, nor oxidation of intracellular dichlorodihydrofluorescein subsequent to H 2O 2 treatment. Consistent with a reduction in apoptotic death, the increase in caspase-3 activity associated with dopamine treatment was also prevented by DATN. These observations suggest that DATN may act to prevent one of the pathways linking dopamine and oxidative stress to caspase-3 activation. We propose that the inhibition of substrate arylation by the products of dopamine oxidation may provide a useful strategy for the prevention of dopamine-induced cell death.

Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus.

The dentate gyrus (DG) is one of the few regions in the brain that continues to produce new neurons throughout adulthood. Seizures not only increase neurogenesis, but also lead to death of DG neurons. We investigated the relationship between cell death and neurogenesis following seizures in the DG of adult rats by blocking caspases, which are key components of apoptotic cell death. Multiple intracerebroventricular infusions of caspase inhibitors (pancaspase inhibitor zVADfmk, and caspase 3 and 9 inhibitor) prior to, just after, 1 day after, and 1 week following 2 h of lithium-pilocarpine-induced status epilepticus reduced the number of terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelled (TUNEL) cells and increased the number of bromodeoxyuridine (BrdU) -stained proliferated cells in the subgranular zone at 1 week. The caspase inhibitor-treated group did not differ from control at 2 days or 5 weeks following the epileptic insult. Our findings suggest that caspases modulate seizure-induced neurogenesis in the DG, probably by regulating apoptosis of newly born neurons, and that this action can be suppressed transiently by caspase inhibitors. Furthermore, although previous studies have indicated that increased neuronal death can trigger neurogenesis, we show here that reduction in apoptotic death may be associated with increased neurogenesis.