Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes.

In T lymphocytes, the role of Akt in regulating Fas/Fas ligand (FasL)-mediated apoptotic signaling and death is not clearly understood. In this study, we observed that inhibition of Akt causes enhanced expression of FasL mRNA and protein and increased death-inducing signaling complex (DISC) formation with Fas-associated death domain (FADD) and procaspase-8 recruitment. Also, caspase-8 was activated at the DISC with accompanying decrease in c-FLIPs expression. FasL neutralizing antibody significantly decreased apoptotic death in the Akt-inhibited T cells. Additionally, Akt inhibition-induced Fas signaling was observed to link to the mitochondrial pathway via Bid cleavage. Further, inhibition of caspase-8 activity effectively blocked the loss of mitochondrial membrane potential and DNA fragmentation, suggesting that DISC formation and subsequent caspase-8 activation are critical initiating events in Akt inhibition-induced apoptotic death in T lymphocytes. These data demonstrate yet another important survival function governed by Akt kinase in T lymphocytes, which involves the regulation of FasL expression and consequent apoptotic signaling.

Comparative values of erythrocyte aggregability versus other indices of hemorheological disorders in patients with ischemic brain infarcts.

The aim of the present study is comparison of changes of principal hemorheological factors responsible for blood flow disorders in the microcirculation in patients with ischemic brain infarcts. It was found that in venous blood samples the erythrocyte aggregability (examined with a direct, highly sensitive, quantitative technique) was considerably more increased (by mean of 120%) than the blood plasma fibrinogen contents, blood plasma viscosity, and hematocrit which increased only by 23.7%, 7.4% and 3.6%, respectively, as compared to the same hemorheological factors in the healthy controls. These results led us to the following conclusion: among the other tests the enhanced erythrocyte aggregability, when measured with an appropriate technique, is the best diagnostic indicator of hemorheological derangements during development of the ischemic brain infarct.

Microcirculatory stasis induced by hemorheological disorders: further evidence.

OBJECTIVE: Reinvestigate the microcirculatory alterations immediately responsible for blood rheological disorders and blood stases, which are related to red blood cell (RBC) aggregation in capillaries. METHODS: Blood rheological disorders were produced by significantly intensified intravascular red blood cell aggregation in the intestinal mesentery of Wistar rats and in the cerebral cortex of Chinchilla rabbits, either systemically (by intravascular administration of high molecular-weight dextran) or locally (by increase of high-molecular compounds in blood plasma inside individual or groups of capillaries). RESULTS: Under conditions where the microvascular lumina were not decreased and the arteriolovenular pressure gradients got even higher, the significantly enhanced intravascular RBC aggregation resulted in the slowing down of blood flow in the microvessels to a full stop. CONCLUSION: A significant increase in microvascular RBC aggregation results in local hemorheological disorders, which is, in all probability, related to derangement of the blood-flow structuring in microvessels.

New evidence for involvement of blood rheological disorders in rise of peripheral resistance in essential hypertension.

To ascertain the contribution of blood rheological disorders in elevation of arterial pressure during hypertension, erythrocyte aggregability was investigated in rats and evaluated in patients with the Georgian technique. The evidence obtained for the significant role that blood rheological disorders play in development of this pathological phenomenon was found to be as follows: (a) the enhanced erythrocyte aggregation in rat's blood (caused by high molecular weight dextran administration) results in a rise of the systemic arterial pressure while the arteriolar diameters remain unchanged; (b) a direct relationship has been found between the index of erythrocyte aggregability (Georgian technique) and total peripheral resistance in patients with mild and severe forms of the essential hypertension; and (c) a linear relationship between lowering of erythrocyte aggregability and the diastolic arterial pressure, as well as total peripheral resistance, was revealed also following treatment of hypertensive patients with Ca-antagonists. These findings support the conclusion that blood rheological disorders, related to increased erythrocyte aggregability, play a significant role in the concerted action of factors enhancing peripheral resistance and in elevation of the arterial pressure in patients with essential hypertension.

Effect of intensified red blood cell aggregability on arterial pressure and mesenteric microcirculation.

Intensified aggregability of red blood cells (RBC) was produced in adult white rats by the step-by-step intravascular administration of a high-molecular-weight dextran, with a molecular weight approximating that of blood fibrinogen. As a result, the systemic arterial pressure was elevated by more than one-third of the initial level, whereas the diameter of arterioles in the intestinal mesentery remained practically unchanged. This provided sufficient grounds for the conclusion that the increase in the total peripheral resistance was due to disturbances in blood rheological properties. Despite the elevated arterial pressure, the blood flow velocity in mesenteric arterioles displayed a clear-cut tendency to slow down. Simultaneously, a large number of RBC aggregates appeared in the mesenteric microvessels. In patients with a stable form of arterial hypertension the RBC aggregability index was found to be significantly increased as compared with that of the healthy control group. Following treatment with Ca(2+)- and beta-adrenergic blockers the index decreased significantly in parallel with the lowering of arterial pressure. The obtained results suggest that the intensified RBC aggregation in microvessels causing a disturbance of normal blood flow structure, and hence of blood rheological properties, might be an important factor responsible for the elevation of systemic arterial pressure in humans with arterial hypertension.