INFLAMMATORY CYTOKINES CAUSE CORONARY ARTERIOSCLEROSIS-LIKE CHANGES AND ALTERATIONS IN THE SMOOTH-MUSCLE PHENOTYPES IN PIGS

We recently developed a porcine model in which chronic, local treatmen t with interleukin-1 beta (IL-1 beta) causes coronary arteriosclerosis -like changes and hyperconstrictive responses. This study was designed to examine whether or not other major inflammatory cytokines [tumor n ecrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha)] might also cause similar coronary responses and whether those respons es are associated with alterations in the smooth-muscle phenotypes. A segment of the porcine coronary artery was aseptically wrapped with co tton mesh, absorbing IL-1 beta, TNF-alpha, and IL-1 alpha. Two weeks a fter the operation, coronary arteriography showed the development of m ild stenotic lesions at the cytokine-treated sites, where hyperconstri ctive responses were repeatedly induced by intracoronary serotonin or histamine. Histologically mild intimal thickening was noted at those c ytokine-treated sites. Immunostaining and immunoblotting demonstrated that all three myosin heavy chain isoforms, SM1, SM2 (smooth-muscle ty pe), and SMemb (nonmuscle type), were noted in the normal coronary seg ments, whereas in the segments treated with inflammatory cytokines, SM I and SM2 were markedly reduced, and only SMemb was noted. These resul ts indicate that inflammatory cytokines all have a similar ability to induce coronary arteriosclerosis-like changes and hyperconstrictive re sponses, which are associated with alterations in smooth-muscle phenot ypes toward dedifferentiation.