Protein kinase C mediates basic fibroblast growth factor-induced proliferation through mitogen-activated protein kinase in coronary smooth muscle cells.

Proliferation of coronary smooth muscle cells (cSMCs) contributes to the pathogenesis of arteriosclerosis and restenosis after angioplasty, and basic fibroblast growth factor (bFGF) is a powerful mitogen for cSMCs. In this study, we investigated the involvement of mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and the transcription factor c-myc in bFGF-stimulated mitogenesis, as well as the functional relationship between these factors. cSMC stimulation with bFGF resulted in phosphorylation of p42 MAPK, as well as the phosphorylation and increased expression of c-myc. The MAPK kinase (MEK) inhibitor PD98059 blocked bFGF-stimulated MAPK phosphorylation and resulted in both a decrease of c-myc expression and inhibition of bFGF-stimulated DNA synthesis in cSMCs. bFGF also increased PKC activity in cSMCs in a time-dependent manner. The inhibition of PKC by chelerythrine or its downregulation by phorbol 12-myristate 13-acetate (PMA) inhibited bFGF-induced DNA synthesis and blocked the phosphorylation of MAPK and c-myc expression in response to bFGF. This indicates an involvement of phorbol ester-sensitive PKC isoforms in MAPK activation and mitogenic signaling by bFGF. Western blot analysis revealed the presence of the phorbol ester-sensitive isoforms PKC alpha, epsilon, and gamma as well as the PKC isoforms iota, lambda, micro, and zeta in cSMCs. In this study, we show that the MAPK cascade is required for bFGF-induced proliferation and that phorbol ester-sensitive PKC isoforms contribute to the bFGF-induced cSMC mitogenesis in cSMCs.

[Severity of angina pectoris and coronary angiographic imaging]. / Nasilenie dusznicy bolesnej a obraz koronariograficzny naczyn wiencowych.

The aim of the study was to evaluate commonly accepted assumption that more extensive coronary lesions correspond to more severe coronary symptoms. 300 consecutive patients with coronary artery disease (74 women and 226 men) admitted to Department of Coronary Disease in 1993/94 were studied. Coronary symptoms were assessed according to the Canadian Cardiovascular Society (CCS) classification of angina pectoris. Anatomic lesions revealed by angiography were classified as one, two or three vessel disease and also with use of Califfs jeopardy score (0-12 points) which is the simple and more precise method of estimating the amount of myocardium at risk. We found significant but rather weak correlation between severity of coronary symptoms (CCS) and angiographic findings (jeopardy score): (r = 0.16, p = 0.07). It was shown that there is the significant correlation between symptoms severity and anatomic lesions revealed by angiography. 17% of patients in spite of the extensive coronary atherosclerosis (10-12 points according to Califf) were almost asymptomatic (I class CCS). It is emphasized that one third of the patients had no critical stenosis however 51% of them presented severe coronary symptoms (III, IV class CCS).

An inhibitory effect of camonagrel-a new thromboxane synthase inhibitor, on P-selectin-mediated platelet/PMN adhesion.

P-selectin (PADGEM protein, GMP-140 or CD 62) is a glycoprotein of platelet a-granules and endothelial Weibel-Palade bodies that, by mediating cellular adhesion, initiates recruitment of leukocytes and lymphocytes into injured tissue. Both of the endothelial antiplatelet autacoids prostacyclin (PGI(2)) and nitric oxide (NO) have been demonstrated to inhibit P-selectin expression. Prostaglandin endoperoxides PGG(2)/PGH(2) that are generated by activated platelets have been demonstrated to be used by endothelium for generation of prostacyclin. In an experimental model in vitro that resembles vessel wall/platelet/PMN interaction in vivo, we found that aspirin (100 µM), a COX inhibitor, but not L-NMMA (100 µM) and a NO-synthase inhibitor, reversed the inhibitory effect of arterial wall on P-selectin mediated platelet/PMN adhesion. The anti-adhesive potency of vessel wall reversed by aspirin was dose-dependently restored by camonagrel (3-100 µM), a new TXA(2) synthase inhibitor. We conclude that selective TXA(2)-synthase inhibitors may inhibit P-selectin mediated platelet/PMN adhesion by augmenting formation of prostacyclin by vessel walls.