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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.06.009 Byline: Yu Liu (a), Zuyi Yuan (a)(b), Yan Liu (a), Jijun Zhang (a), Ping Yin (a), Dongqi Wang (a), Yanni Wang (a), Chiharu Kishimoto (c), Aiqun Ma (a)(b) Abstract: Peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) is a transcription factor implicated in the expression of proinflammatory cytokines in atheroma-associated cells, and the expression of proinflammatory cytokines, such as tumor necrosis factor [alpha] (TNF-[alpha]) and matrix metalloproteinases (MMPs), represents a critical step in atherogenesis and atherosclerosis. In this study, we test the hypothesis of whether a polymorphism corresponding to C161T substitution in exon 6 of the PPAR[gamma] gene may affect the expression of proinflammatory cytokines and the onset of coronary artery diseases (CADs) in a Chinese population. Author Affiliation: (a) Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China (b) Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, China (c) Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan Article History: Received 5 January 2005; Accepted 15 June 2007 Article Note: (footnote) This study was supported in part by the Natural Science Foundation of China (NSFC, Chian 30170371, 30570732).

In this study, we tested the hypothesis that MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one; edaravone), a novel free radical scavenger, protects against acute experimental autoimmune myocarditis (EAM) in rats by the radical scavenging action associated with the suppression of cytotoxic myocardial injury. Recent evidence suggests that oxidative stress may play a role in myocarditis. We administered MCI-186 intraperitoneally at 1, 3, and 10 mg*[kg.sup.-1]*[day.sup.-1] to rats with EAM for 3 wk. The results were compared with untreated rats with EAM. MCI-186 treatment did not affect hemodynamics. MCI-186 treatment (3 and 10 mg*[kg.sup.-1]*[day.sup.-1]) reduced the severity of myocarditis as assessed by comparing the heart-to-body weight ratio and pathological scores. Myocardial interleukin-1[beta] (IL-1[beta])- positive ceils and myocardial oxidative stress overload with DNA damage in rats with EAM given MCI-186 treatment were significantly less compared with those of the untreated rats with EAM. In addition, MCI-186 treatment decreased not only the myocardial protein carbonyl contents but also the myocardial thiobarbituric acid reactive substance products in rats with EAM. The formation of hydroxyl radicals in MCI-186-treated heart homogenates was decreased compared with untreated heart homogenates. Furthermore, cytotoxic activities of lymphocytes of rats with EAM treated with MCI-186 were significantly lower compared with those of the untreated rats with EAM. Hydroxyl radicals may be involved in the development of myocarditis. MCI-186 protects against acute EAM in rats associated with scavenging hydroxyl free radicals, resulting in the suppression of autoimmune-mediated myocardial damage associated with reduced oxidative stress state. lymphocytes; immune system; inflammation

Some ANG II receptor type 1 (A[T.sub.1]) antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. However, the effects of the drugs on autoimmune diseases are unknown. We tested the hypothesis that olmesartan, a novel A[T.sub.1] antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributed to the suppression of inflammatory cytokines as well as to the immunomodulatory action of the heart. We administered olmesartan orally at does of 1, 3, and 10 mg x [kg.sup.-1] x [day.sup.-1] to rats with EAM for 3 wk. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group and markedly reduced the severity of myocarditis associated with the decrease of myocardial macrophage, CD[4.sup.+], and CD[8.sup.+] T-cell expression by comparison of heart wt-to-body wt ratios, pericardial effusion scores, and macroscopic and microscopic scores. Numbers of myocardial interleukin-1[beta] (IL-1[beta])-positive-staining cells (obtained by immunohistochemistry) and quantities of IL-1[beta] expression (obtained by Western blotting) were significantly lower in rats with EAM given olmesartan treatment compared with rats given vehicle. Cardiac myosin-specific, delayed-type hypersensitivity was significantly lower in olmesartan-treated rats than in control rats. The cytotoxic activities of lymphocytes in rats with EAM treated with olmesartan were reduced compared with untreated control rats. In vitro study showed that both olmesartan and its active metabolite RNH-6270 suppressed IL-1[beta] production in U-937 cells and cultured myocytes. Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines as well as to suppressive effects of cytotoxic myocardial injury in addition to hemodynamic modifications. angiotensin II type 1; inflammation; cardiomyopathy; myocarditis

We investigated the suppressive effects of immunoglobulin (Ig) on effector T cells in autoimmune myocarditis. Treatment with Ig reduced production of the so-called T-helper type 1 (Th 1) cytokines stimulated by concanavalin A or cardiac myosin in cultured lymph node (LN) cells from rats with myocarditis. The cytotoxic activities of LN cells from rats immunized with myosin and treated with Ig were reduced against cardiomyocytes and F-2 cells compared with those treated without Ig. The adoptive transfer of myocarditis from LN ceils of Lewis rats with myocarditis to severe combined immunodeficient (SCID) recipients was successfully achieved. Treatment with Ig, but not with F[(ab').sub.2] fragments of Ig, reduced the mortality and severity of myocarditis in SCID recipient mice. Decreased ability of LN cells of Ig-treated rats, but not rats treated with F[(ab').sub.2] fragments, to transfer autoimmune myocarditis was also demonstrated. The findings of the present study suggest that autoimmune myocarditis was successfully transferred to SCID mice and that treatment with Ig ameliorated autoimmune myocarditis by inducing selective myosin unresponsive- ness via the Fc portion, resulting in suppression of Th1 cytokine production and cytotoxic activities of LN cells, which operated together in the development of autoimmune myocarditis. lymphocytes; immunity; inflammatory disease

Carvedilol, a new [beta]-blocker with antioxidant properties, has been shown to be cardioprotective in experimental models of myocardial damage. We investigated whether carvedilol protects against experimental autoimmune myocarditis (EAM) because of its suppression of inflammatory cytokines and its antioxidant properties. We orally administered a vehicle, various doses of carvedilol, racemic carvedilol [R(+)-carvedilol, an enantiomer of carvedilol without [beta]-blocking activity], metoprolol, or propranolol to rats with EAM induced by porcine myosin for 3 wk. Echocardiographic study showed that the three [beta]-blockers, except R(+)-carvedilol, suppressed left ventricular fractional shortening and decreased heart rates to the same extent. Carvedilol and R(+)-carvedilol, but not metoprolol or propranolol, markedly reduced the severity of myocarditis at the two different doses and suppressed thickening of the left ventricular posterior wall in rats with EAM. Only carvedilol suppressed myocardial mRNA expression of inflammatory cytokines and IL-1[beta] protein expression in myocarditis. In addition, carvedilol and R(+)-carvedilol decreased myocardial protein carbonyl contents and myocardial thiobarbituric acid-reactive substance products in rats with EAM. The in vitro study showed that carvedilol and R(+)-carvedilol suppressed IL-1[beta] production in LPS-stimulated U937 cells and that carvedilol and R(+)-carvedilol, but not metoprolol or propranolol, suppressed thiobarbituric acid-reactive substance products in myocardial membrane challenged by oxidative stress. It was also confirmed that probucol, an antioxidant, ameliorated EAM in vivo. Carvedilol protects against acute EAM in rats, and the superior cardioprotective effect of carvedilol compared with metoprolol and propranolol may be due to suppression of inflammatory cytokines associated with the antioxidant properties in addition to the hemodynamic modifications. myocarditis; [beta]-blocker

Atherosclerosis is associated with immune activation. Immunoglobulin is used for the treatment of immune-mediated diseases. The mechanisms and importance of the Fc portion of immunoglobulin upon experimental atherosclerosis in apolipoprotein E-deficient mice were examined. Experimental atherosclerosis was induced in mice fed a high-fat diet containing 0.3% cholesterol. Over 8, 12, and 16 wk, on alternate days, mice were treated with an intraperitoneal injection of either 1 g*[kg.sup.-1]*[day.sup.-1] of human intact immunoglobulin or [F(ab').sub.2] fragments of human immunoglobulin. Fatty streak formation and fibrofatty plaques were markedly suppressed in mice that received intact immunoglobulin for 8, 12, and 16 wk. In contrast, atherosclerotic lesions were not ameliorated in mice that received [F(ab').sub.2] fragments. Immunohistochemical analysis revealed that macrophage accumulation in the fatty streak lesions was suppressed in mice received intact immunoglobulin but not in those that received [F(ab').sub.2] fragments. In addition, the cytotoxic activities of splenocytes from immunoglobulin-treated mice, but not from [F(ab').sub.2] fragment-treated mice, were significantly suppressed compared with those from human serum albumin-treated mice. Differences in lesion area did not correlate with any significant alterations in serum lipid levels. Immunoglobulin therapy markedly suppressed atherosclerosis due to Fc receptor-mediated anti-inflammatory and immunomodulating actions. The antiatherosclerotic effects of immunoglobulin may be related to the suppression of cytotoxic activity of atherogenic T cells and the reduction of macrophage accumulation in the lesions. knockout mice; Fc receptor

Cocksakievirus B3 (CB3)-infected mice were analyzed after the administration of captopril to determine the effects of the angiotensin-converting enzyme (ACE) on interstitial inflammatory fibrin deposition. Inflammatory fibrin deposition, ventricular remodeling and postmyocarditic myocyte hypertrophy was inhibited by the administration of captopril in CB3-infected mice. Furthermore, captopril maintained connective tissue architecture and suppressed myosin isoform shift in CB3-infected mice.