Carvedilol improves left ventricular function in murine coxsackievirus‐induced acute myocarditis Association with reduced myocardial interleukin‐1β and MMP‐8 expression and a modulated immune response

Abstract

Background: Proinflammatory cytokines induce the expression of matrix metalloproteinases that play a crucial role in myocardial remodeling. Beta-adrenergic receptor stimulation influences the production of cytokines heralding the possibility of modulating cytokine production by beta-adrenergic blockers. Methods and results: In a coxsackievirus B3 murine myocarditis model (BALB/c), effects of carvedilol and metoprolol on myocardial cytokine expression, inflammatory cell infiltration and MMP/TIMP profiles were investigated. In carvedilol-treated mice, a significant improvement in left ventricular function was documented 10 days post infection. In infected mice (n=10), IL-1h, TNF-a, TGF-h 1 and IL-10 myocardial mRNA abundance were increased significantly (240%, 200%, 161%, and 230%) compared to controls (n=10), while IL-15 mRNA was markedly reduced (70%). Infected mice showed significantly increased infiltrations with CD3-, CD4-and CD8-T-lymphocytes (730%, 1110%, 380%). In the infected mice, myocardial MMP/TIMP profiles presented a significant upregulation of membrane type-1 MMP, MMP-9, MMP-8 and MMP-3 (150%, 160%, 340%, and 270%) and a significant decrease in TIMP-4 levels (75%). Carvedilol attenuated over-expression of myocardial TGF-h 1 , IL-1h and MMP-8 mRNA expression significantly and induced a relevant IL-10 mRNA expression in the infected mice (n=10). By an unchanged infiltration with CD3-T-lymphocytes, carvedilol showed a representative reduction in CD4-T-lymphocytes. Conclusion: Carvedilol treatment in experimental myocarditis leads to reduced expression of proinflammatory cytokines and MMPs, which contributes to reduced matrix degradation and ultimately to improved structural integrity of the heart. Besides the antiadrenergic potential, carvedilol is beneficial due to a wide range of biological activities (antiinflammatory, antifibrotic, antioxidative and immunomodulatory).

Myeloid Differentiation Factor-88/Interleukin-1 Signaling Controls Cardiac Fibrosis and Heart Failure Progression in Inflammatory Dilated Cardiomyopathy

“…On the one hand, it mediates activation of APCs and expansion of the self-pathogenic heart-specific CD4 ϩ T-cell subset promoting myocarditis 16,34 ; on the other hand, it promotes fibrosis and heart failure progression at later stages of disease. This idea might explain why increased levels of il-1␤ transcripts in the myocardium show a linear correlation with cardiac function in coxsackievirus-mediated murine myocarditis 35 and the observation that the local expression of an IL-1R antagonist improves survival in the same model. 36 In our model, the MyD88-dependent signaling appears to be the principle mediator of the development of postinflammatory heart failures.…”

Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

“…Beta-blockers possess antioxidant, anti-proliferative, and free radical scavenging effects, which may alter MMP abundance [123]. Carvedilol reduces plasma MMP-9 levels in younger patients with idiopathic dilated cardiomyopathy and improves LV remodeling in a mouse model of acute myocarditis [124,125]. While carvedilol has been shown to inhibit MMP-2 and -9, it also increases MMP-8 and -13, indicating that the connection between blockers and MMP activity is complex [126,127].…”

Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral Myocarditis

“…RT-PCR was used to detect and semiquantify the mRNA abundance of uPA, tissue plasminogen activator (tPA), MMP-2, MMP-3, MMP-8, MMP-9, MMP-13, TIMP-1, TIMP-2, TIMP-3, TIMP-4, interleukin (IL)-1␤, IL-6, and transforming growth factor (TGF)-␤ 1 based on methods described previously. 10,14 Adenoviral Gene Transfer of TIMP-1 and PAI-1…”