Clinical & Experimental Cardiology
Open Access
ISSN: 2155-9880
+44 1300 500008
ISSN: 2155-9880
+44 1300 500008
Jeffrey R Bender
Yale University School of Medicine, USA
Keynote: J Clin Exp Cardiolog
Cardiovascular physiology and pathology involves the expression of angiogenic, proteolytic and inflammatory genes in a wide variety of contexts. Many of the RNA transcripts encoding these gene products are very labile, leading to minimal gene expression, unless the mRNA is protected from degradation (stabilized). Leukocyte recruitment to, and localization in, many tissues requires the engagement of integrin adhesion receptors, promoting leukocyte adhesion to the endothelium and transmigration into tissues. In both innate (monocyte/macrophage) and adaptive (T lymphocyte) immune cells, engagement of the beta2 integrin LFA-1 results in the rapid and dramatic modulation of an important mRNA-binding protein, HuR, leading to protection of labile transcripts from degradation, and prolongation of their half-lives with enhanced gene expression. Monocyte/macrophages are important producers of the key angiogenic/arteriogenic factor VEGF-A, which is encoded by a transcript that is intrinsically unstable. Integrin engagement in human and mouse macrophages results in marked, HuRdependent stabilization of the VEGF-A mRNA. The signal transduction cascade downstream of integrin engagement includes activation of the small Rho family GTPase Rac2, and its consequent interaction with the non-muscle myosin IIA (MyIIA). Using the murine model of hindlimb ischemia, a powerful model for the study of arteriogenic responses to ischemia, and targeting either Rac2 or MyIIA selectively in macrophages, we showed that a complete revascularizing, arteriogenic response to ischemia requires macrophage Rac2 and MyIIA. Animals with either of these genes deleted in a myeloid-specific fashion have impaired arteriogenic responses to ischemia, as detected by laser Doppler flow imaging. This was not due to failed tissue localization of macrophages, but to their inability to produce angiogenic factors at sufficient levels. Using a different model of inflammation, the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, which involves profound CNS immune/inflammatory reactions mediated largely by the Th17 subset of T lymphocytes, we showed that CNS production of a potent pro-inflammatory cytokine, IL-17A, requires integrin-mediated, HuR-dependent stabilization of its transcript. Mice with Th17-targeted deletion of HuR are completely protected against the development of EAE, with greatly reduced CNS levels of IL-17A mRNA and protein, despite equal numbers of localizing immune cells. In this presentation, a major molecular switch for the production of angiogenic, immune and proteolytic genes in vascular and target organ inflammatory environments is described. This defines a new therapeutic target for the inflammatory component of cardiovascular disease.
Jeffrey R. Bender graduated from the University of California, San Francisco School of Medicine in 1979. He works in New Haven, CT and specializes in Cardiovascular Disease. Jeffrey R. Bender is affiliated with Yale New Haven Hospital.
Email: jeffrey.bender@yale.edu