Tomosaburo Takahashi

Increasing cAMP antagonizes hypertrophic response to angiotensin II without affecting Ras and MAP kinase activation in vascular smooth muscle cells

Angiotensin II (Ang II), a potent hypertrophic factor for vascular smooth muscle cells (VSMC), induces activation of the ras proto‐oncogene product (Ras) and mitogen‐activated protein (MAP) kinases, and tyrosine phosphorylation of a focal adhesion‐associated protein, paxillin. Forskolin, a direct activator of adenylate cyclase, and dibutyryl cAMP (Bt2 cAMP), a membrane permeable cAMP analogue, potently inhibited Ang II‐stimulated protein synthesis. However, they did not inhibit Ang II‐induced activation of Ras and MAP kinases. Although both forskolin and Bt2 cAMP potently reduced background tyrosine phosphorylation of paxillin, they allowed Ang II to induce the same reaction. These results indicate that increasing cAMP antagonizes the hypertrophic response to Ang II without affecting Ras and MAP kinase activation in VSMC and suggest that it does not interrupt signaling from the Ang II receptor to focal adhesions.

Chylomicron remnant induces apoptosis in vascular endothelial cells.

Chylomicron remnant (CR) is a cholesteroland apoE-enriched particle derived from the lipolytic processing of intestinal chylomicron, and has been regarded as an atherogenic lipoprotein in postprandial hyperlipidemia.1,2 However, little is known about the mechanisms through which CR promotes atherosclerosis. Recent studies suggest that remnant lipoproteins induce vascular endothelial dysfunction assessed by measuring endothelium-dependent vasorelaxation.3 Endothelial injury and dysfunction induced by atherogenic lipoprotein are believed to play pivotal roles in atherogenesis. Apoptosis in endothelial cell is considered to be involved in this process.4,5 This hypothesis is supported by the findings that proatherosclerotic factors, such as oxidized low density lipoprotein (LDL), reactive oxygen species, and inflammatory cytokines, have all been shown to induce apoptosis of vascular endothelial cells.6,7 We postulated that CR may promote atherosclerosis by inducing apoptosis in vascular endothelial cells. To examine our hypothesis, we isolated CR and investigated whether CR induces apoptosis in vascular endothelial cells in vitro.

Participation of reactive oxygen intermediates in the angiotensin II-activated signaling pathways in vascular smooth muscle cells.

Angiotensin II (Ang II), the main peptide hormone of the renin-angiotensin system, has been known to play an important role in the development of various cardiovascular diseases in addition to its key regulatory role in the regulation of blood pressure and circulating volume.1 Although Ang II is a potent hypertrophic factor for vascular smooth muscle cells (VSMC),1 molecular mechanisms responsible for a growth-promoting action of Ang II have not been fully understood. Recent studies suggest that reactive oxygen intermediates (ROI) may function as second messengers in the intracellular signaling pathways that mediate cellular responses induced by growth factors and cytokines.2 Therefore, we examined whether ROI were involved in Ang II–activated signaling pathways in cultured VSMC.