epidermal-growth-factor and Coronary-Disease

Topics: Biomarkers; Coronary Disease; Cystitis, Interstitial; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Gastrointestinal Tract; Heparin-binding EGF-like Growth Factor; Hepatectomy; Humans; Intercellular Signaling Peptides and Proteins; Liver Regeneration; Obesity; Pregnancy

Rupture of atherosclerotic plaques is the major cause of acute coronary events (CEs). Plaque destabilization is the consequence of an imbalance between inflammatory-driven degradation of fibrous tissue and smooth muscle cell-dependent tissue repair. Proinflammatory factors have been documented extensively as biomarkers of cardiovascular risk but factors that contribute to stabilization of atherosclerotic plaques have received less attention. The present study aimed to investigate whether plasma levels of the smooth muscle cell growth factor epidermal growth factor (EGF), heparin-binding-EGF (HB-EGF), and platelet-derived growth factor correlate with plaque phenotype and incidence of CEs.. HB-EGF, EGF and platelet-derived growth factor were measured in plasma from 202 patients undergoing carotid endarterectomy and in 384 incident CE cases and 409 matched controls recruited from the Malmö Diet and Cancer cohort. Significant positive associations were found between the plasma levels of all 3 growth factors and the collagen and elastin contents of the removed plaques. CE cases in the Malmö Diet and Cancer cohort had lower levels of HB-EGF in plasma, whereas no significant differences were found for EGF and platelet-derived growth factor. After adjusting for cardiovascular risk factors in a Cox proportional hazard model, the hazard ratio for the highest HB-EGF tertile was 0.61 (95% confidence interval, 0.47-0.82; P<0.001).. The associations between high levels of smooth muscle cell growth factors in plasma and a more fibrous plaque phenotype as well as the association between low levels of HB-EGF and incident CEs point to a potential clinically important role for factors that contribute to plaque stabilization by stimulating smooth muscle cells.

Topics: Aged; Aged, 80 and over; Biomarkers; Carotid Artery Diseases; Case-Control Studies; Coronary Disease; Endarterectomy, Carotid; Epidermal Growth Factor; Female; Heparin-binding EGF-like Growth Factor; Humans; Incidence; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Muscle, Smooth, Vascular; Phenotype; Plaque, Atherosclerotic; Platelet-Derived Growth Factor; Proportional Hazards Models; Prospective Studies; Protective Factors; Risk Assessment; Risk Factors; Rupture, Spontaneous; Sweden; Up-Regulation

A single nucleotide polymorphism that substitutes a serine for an asparagine at residue 700 in the Ca2+-binding repeats of thrombospondin-1 is associated with familial premature coronary heart disease. We expressed the Ca2+-binding repeats alone (Ca) or with the third epidermal growth factor-like module (E3Ca), without (Asn-700) or with (Ser-700) the disease-associated polymorphism. The intrinsic fluorescence of a single tryptophan (Trp-698) adjacent to the polymorphic residue was quenched cooperatively by adding Ca2+. The third epidermal growth factor-like repeat dramatically altered the Ca2+-dependent fluorescence transition for the Asn-700 constructs; the half-effective concentration (EC50) of Ca Asn-700 was 390 microM, and the EC50 of E3Ca Asn-700 was 70 microM. The Ser-700 polymorphism shifted the EC50 to higher Ca2+ concentrations (Ca Ser-700 EC50 of 950 microM and E3Ca Ser-700 EC50 of 110 microM). This destabilizing effect is due to local conformational changes, as the Ser-700 polymorphism did not influence the secondary structure of E3Ca or Ca as assessed by far UV circular dichroism. At 200 microM Ca2+, in which both E3Ca Asn-700 and Ser-700 are in the Ca2+-replete conformation at 37 degrees C, the fluorescence of E3Ca Ser-700 reverted to the Ca2+-depleted spectrum at 50 degrees C compared with 65 degrees C for E3Ca Asn-700. These findings indicate that the Ser-700 polymorphism subtly but significantly sensitizes the calcium-binding repeats to removal of Ca2+ and thermal denaturation.

Topics: Calcium; Circular Dichroism; Cloning, Molecular; Coronary Disease; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Epidermal Growth Factor; Humans; Polymorphism, Genetic; Protein Binding; Protein Conformation; Protein Denaturation; Protein Structure, Tertiary; Recombinant Proteins; Serine; Spectrometry, Fluorescence; Temperature; Thrombospondin 1; Tryptophan; Ultraviolet Rays