Previous studies showed that the epidermal growth factor receptor (EGFR) can be transactivated by platelet-derived growth factor (PDGF) stimulation and that EGFR transactivation is required for PDGFstimulated cell migration. To investigate the mechanism for cross talk between the PDGF ␤ receptor (PDGF␤R) and the EGFR, we stimulated rat aortic vascular smooth muscle cells (VSMC) with 20 ng of PDGF/ml. Transactivation of the EGFR, defined by receptor tyrosine phosphorylation, occurred with the same time course as PDGF␤R activation. Basal formation of PDGF␤R-EGFR heterodimers was shown by coimmunoprecipitation studies, and interestingly, disruption of this receptor heterodimer abolished EGFR transactivation. Breakdown of the heterodimer was observed when VSMC were pretreated with antioxidants or with a Src family kinase inhibitor. Disruption of heterodimers decreased ERK1 and ERK2 activation by PDGF. Although PDGF-induced PDGF␤R activation was abolished after pretreatment with 1 M AG1295 (a specific PDGF receptor kinase inhibitor), EGFR transactivation was still observed, indicating that PDGF␤R kinase activity is not required. In conclusion, our data demonstrate that the PDGF␤R and the EGFR form PDGF␤R-EGFR heterodimers basally, and we suggest that heterodimers represent a novel signaling complex which plays an important role in PDGF signal transduction.

The extent of myocardial damage contributes to the elevation of serum VEGF levels in AMI. VEGF produced by PBMCs may play an important role in the improvement of left ventricular function by promoting angiogenesis and reendothelialization after AMI.

Critical events for vasoconstrictor and growth factor signal transduction include stimulation of phospholipase C␥ (PLC␥) and elevation of intracellular calcium. c-Src has been proposed as a common mediator for these signals activated by both G protein-coupled receptors (GPCRs) and tyrosine kinase-coupled receptors (TKRs). Here we show that the GPCR kinase-interacting protein-1 (GIT1) is a substrate for c-Src that undergoes tyrosine phosphorylation in response to angiotensin II (AngII) and EGF in vascular smooth muscle and 293 cells. GIT1 associates with PLC␥ via the PLC␥ Src homology 2 and 3 domains constitutively, and the interaction is unaltered by AngII and EGF. GIT1 interaction with PLC␥ is required for PLC␥ activation based on inhibition of tyrosine phosphorylation and calcium mobilization after GIT1 knockdown with antisense GIT1 oligonucleotides. GIT1 interacts with PLC␥ via a novel Spa homology domain (SHD) and a coiled-coil domain. Deletion mutation analysis showed that GIT1(SHD) is required for AngII-and EGF-mediated PLC␥ activation (measured by phosphorylation of Tyr 783 and inositol 1,4,5-trisphosphate formation). We propose that GIT1 is a novel regulator of PLC␥ function that mediates PLC␥ activation by c-Src and integrates signal transduction by GPCRs and TKRs.

Older age, beta-blocker use, and regular alcohol drinking were significant determinants of the exaggerated ME difference in medicated hypertensive patients.

Objective-To investigate changes in cytokine expression in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA). Methods-The study involved 32 patients with ischaemic heart disease who underwent elective PTCA for isolated stenotic lesions of the left coronary artery. Ten patients had plain old balloon angioplasty, 10 had percutaneous transluminal rotational atherectomy, and 12 had stent implantation. Blood samples were drawn from the coronary sinus before and immediately after PTCA. Plasma concentrations of interleukin 6 (IL-6), platelet derived growth factor (PDGF), monocyte chemoattractant protein 1 (MCP-1), and macrophage coronary stimulating factor (M-CSF) were measured. The patients were scheduled for follow up angiography six months after PTCA. Late loss index was calculated using quantitative coronary angiography. Results-IL-6 concentrations in coronary sinus blood increased immediately after PTCA (p < 0.001), but there was no change in PDGF, MCP-1, or M-CSF. There was a positive correlation between changes in IL-6 concentrations immediately after PTCA and late loss index six months after PTCA (r = 0.73, p < 0.001). IL-6 concentrations in coronary sinus blood were higher in patients with late restenosis than in those without restenosis (p < 0.001). Conclusions-PTCA induces IL-6 production in the coronary circulation. This may induce subsequent inflammatory responses in injured vessels and play an important role in late restenosis after PTCA. (Heart 2000;84:83-87)