HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation

Azuma, Ryoko Wakizono; Suzuki, Jun–ichi; Ogawa, Masahito; Futamatsu, Hideki; Koga, Noritaka; Onai, Yasuyuki; Kosuge, Hisanori; Isobe, Mitsuaki

doi:10.1016/j.cardiores.2004.09.014

Cited by 53 publications

(34 citation statements)

References 40 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rats treated with high-dose fluvastatin had improved functional and histologic scores when compared with placebo-treated rats. Fluvastatin inhibits myocardial inflammation by decreasing the production of the Th1 cytokines IFN␥ and IL-2, inhibiting expression of NF-B in the myocardium, decreasing IL-4, IL-6, IL-10, IL-1␤, and TNF␣ transcription in the myocardium, and preventing T helper cells from infiltrating the heart (123).…”

Section: Abeles and Pillingermentioning

confidence: 99%

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Abeles

Pillinger

2006

Arthritis & Rheumatism

136

View full text Add to dashboard Cite

Section: Abeles and Pillingermentioning

confidence: 99%

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Abeles

Pillinger

2006

Arthritis & Rheumatism

136

View full text Add to dashboard Cite

“…This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppression of Th1-type cytokine secretion through a mechanism involving primarily their inhibitory effects on isoprenoid biosynthesis [7,12]. Conversely, atorvastatin does not appear to affect the Th1/Th2 balance either in an experimental autoimmune uveitis mouse model [13] or in autoimmune diabetes in NOD mice [14].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

et al. 2008

View full text Add to dashboard Cite

Statins block the activity of HMG-CoA reductase, which catalyses the production of mevalonate, an intermediate in cholesterol biosynthesis, which is also a precursor of isoprenoids. In addition to lowering circulating cholesterol, these drugs display antiinflammatory and immunomodulatory activities in vitro; however, their effects on the development of adaptive immune responses in vivo, as well as the underlying mechanisms, are as yet largely unknown. Here we investigated the outcome of simvastatin treatment on a number of processes, which together orchestrate adaptive immunity to specific antigen. Simvastatin treatment resulted in a marked reduction of T and B cells in spleen, lymph nodes and peripheral blood in mice. This effect could be ascribed principally to an impairment of lymphocyte homing to secondary lymphoid organs. In addition, simvastatin was found to strongly inhibit T-cell responses to the MHCI restricted hen ovalbumin peptide antigen SIINFEKL and to impair ovalbumin uptake and cross-presentation by MHCI. Simvastatin also suppressed antibody responses to immunization with ovalbumin and delayed-type hypersensitivity to allergens. These activities could be largely accounted for by the simvastatin-dependent inhibition of HMG-CoA reductase. The data provide novel mechanistic insight into the activities of simvastatin in the highly complex context of the immune response.Key words: Apoptosis . Homing . Immune responses . Simvastatin IntroductionStatins are competitive inhibitors of HMG-CoA reductase, a major rate-limiting enzyme that controls HMG-CoA conversion to mevalonic acid in the cholesterol biosynthetic pathway. In addition to lowering circulating cholesterol, statins act as antiinflammatory and immunomodulatory agents [1]. These activities have been largely ascribed to their capacity to block isoprenoid production, and thereby to inhibit prenylation of small Ras superfamily GTPases, which are master regulators of cell activation and proliferation, cytoskeletal remodelling and membrane trafficking [2].Statins suppress T-cell activation both directly and by interfering with APC maturation and function. Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also 2832affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppressio...

show abstract

“…On the basis of the above data and in consideration of the key role played by T helper cells in the pathogenesis of myocarditis, in the last years several authors [16][17][18][19][20][21][22][23][24] investigated the therapeutic potential as well as the putative underlying mechanisms of statin administration in animal models of the disease ( Table 1). The results of these studies, in which different molecules were used (mainly atorvastatin, but also fluvastatin, simvastatin, rosuvastatin and pitavastatin), clearly and consistently demonstrated the ability of this class of drugs to significantly improve both cardiac function, as assessed by echocardiography, and the histopathological severity of the disease, with respect to untreated animals.…”

mentioning

confidence: 99%

“…In turn, these effects finally result in a marked reduction of the amount of cardiac Th1-type and proinflammatory cytokines, thus attenuating their harmful consequences on the myocardium, i.e. cardiomyocyte apoptosis, and structural and electrophysiological remodelling, which are chiefly involved in the severe depression of cardiac function, and the high arrhythmic risk characterizing myocarditis and inflammatory DCM [16][17][18][19][20][21][22][23][24].…”

mentioning

confidence: 99%

Statins as a New Therapeutic Perspective in Myocarditis and Postmyocarditis Dilated Cardiomyopathy

Lazzerini

Capecchi

Laghi-Pasini

2013

Cardiovasc Drugs Ther

View full text Add to dashboard Cite

HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation

Abstract: Fluvastatin ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines via inactivation of nuclear factor-kappaB, and this activity is independent of cholesterol reduction.

Cited by 53 publications

References 40 publications

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

Statins as a New Therapeutic Perspective in Myocarditis and Postmyocarditis Dilated Cardiomyopathy

Contact Info

Product

Resources

About