Gene therapy in coronary angioplasty and bypass

US6335010B1 · kind B1 · utility

Assignee

• The Regents of the University of California at San Diego · US

Inventors

• Shu Chien · Village of La Jolla, US
• John Y-J Shyy · San Diego, US

Key dates

• Filing date: Jun 30, 1997
• Grant date: Jan 1, 2002
• Expiry date: Jun 30, 2017

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61K38/00
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Hemodynamic forces play a key role in inducing 2, theroscler-osis-implicated gene in Vascular endothelial cells. To ellcitate the signal transduction pathway leading to such gene expression, the effects of fluid shearing on the activities of upstream signaling molecules is reported here. Fluid shearing (shear stress=12 dynes/cm2) induced a transient and rapid activation of p21ras and preferentially activated c-jun NH2 terminal kinases (JNK 1, 2) over extracellular signal-regulated kinases (ERK-1, -2). Co-transfection of RasNI7, a dominant negative mutant of Ha-Ras, attenuated the shear-activated JNK and luciferase reporters driven by TPA-responsive elements. JNIK(K-R) and MEKK(K-M), the respective catalytically inactive mutants of JNKI and MEKK, also partially inhibited the shear-induced luciferase reporters. In contrast, Raf301, ERK(K71R), and ERK(K52R), the dominant negative mutants of Raf-1, ERK-1, and ERK-2, respectively, had little effects on the activities of these reporters. The activation of JNK was also correlated with an increased c-Jun transcriptional activity, which was attenuated by a negative mutant of Son of sevenless (Sos). Thus, mechanical stimulation exerted by fl…