The dependence on direct contact led us to propose that trypsin-resistant membrane components or factors released by the maturing GDC-0941 parasite or from the bursting mature schizont, such as lactic acid, glycosylphosphatidylinositol, haemozoin, uric acid, and histones or from factors derived from oxidative stress, induce EC apoptosis. Irrespective of their nature, the apoptogenicity of any soluble factors alone depends on the acidification of the environment, since the induction of apoptosis was not pronounced in co-cultures incubated in culture medium with high buffering capacity. Moreover, we had shown in a previous study that under acidic culture conditions PRBCs are induced to undergo apoptosis. Thus, we cannot dismiss the possibility that factors released from apoptotic PRBCs would also contribute to apoptosis observed in the ECs. At present, the nature of these factors remains a matter for future investigation. From our observation we predict that their production or structure would differ between distinct parasite isolates. PALPFs transcript in several P. falciparum isolates has allowed differentiate its ability to induce EC apoptosis. In our study, when parasite transcript was compared between an EC apoptotic and non apoptotic environment, the result obtained pointed to two PALPFs, described as hypothetical transmembrane proteins: PALF-5, PALF 2. In addition, PF11_0521, a gene for a transmembrane protein belonging to the PfEMP1 var gene family, has also been up regulated in these apoptotic conditions. Variation of the transcription profile of var genes must be interpreted carefully since it can change during clinical isolates adaptation to in vitro culture. In this study, we show another level of complexity in the analysis of transcription profile of this var gene, since it can also change and be up regulated when PRBCs are in a slight acidic environment and in contact with the ECs. Therefore, this study highlights a new aspect in the interaction between the PRBCs and ECs: the environment plays a crucial role in modulating the expression of parasite genes potentially implicated in the EC death. We are aware that the observations presented here derive from three distinct P. falciparum isolates only. Nonetheless, the strikingly distinct patterns of EC death induction are sufficient to formulate a hypothetical framework to account, at least in part, for the complex nature of pathogenesis in malaria, and that would be consistent with long-standing clinical observations and current hypotheses. The notion that P. falciparum strains differ in pathogenicity has found support from epidemiological and experimental observations. Many factors were proposed to account for these differences: variations in multiplication rate, in antigenicity, and in the production and nature of an as yet hypothetical malaria toxin. The discovery of a multigene family of proteins that mediate cytoadherence to distinct endothelial receptors provided a plausible hypothesis whereby the type and severity of the symptoms that might result from infection by a particular isolate would Vorinostat citations depend on the immune selection of subpopulations expressing distinct PfEMP1 proteins which would in turn modify the extent of sequestration to different organs. Our observations suggest another layer of complexity. Each isolate would have a distinct propensity to cause EC apoptosis and subsequent alteration of the endothelial.