Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation

Abstract

Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a nonpsychoactive constituent of marijuana that exerts antiinflammatory effects independent of classical cannabinoid receptors. Recently, 80 clinical trials have investigated the effects of CBD in various diseases from inflammatory bowel disease to graft versus host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received U.S. Food and Drug Administration approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T-cell infiltration, profound inflammatory response and fibrosis (measured by quantitative real-time polymerase chain reaction, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with a pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ T cell-mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation.

Conflict of interest statement

DISCLOSURE

The authors declare that they have no competing interests as defined by Molecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.

Figures

Figure 1.

Effect of CBD on inflammatory cell invasion of the left ventricular myocardium. (A) Representative images of H&E-stained sections of the left ventricle. Magnification: 100×. (B) Representative areas from H&E-stained section with 400× magnification.

Figure 2.

Effects of CBD treatment on inflammatory cell markers in EAM. The graphs show the mRNA gene expression of CD3e, CD3g, CD4, CD8a, Itgax and EmR f4/80 in experimental autoimmune myocarditis. *P < 0.05 versus CTL; #P < 0.05 versus EAM.

Figure 3.

Effects of CBD on inflammatory cytokines in EAM. LV mRNA gene expression of proinflammatory cytokines (IL-6, IFN-γ, IL1β) and chemokines (MCP1) in experimental autoimmune myocarditis. *P < 0.05 versus CTL; #P < 0.05 versus EAM.

Figure 4.

Effects of CBD on oxidative stress and inflammation in EAM. (A) Cardiac mRNA expression of oxidative stress markers (p47phox and SERCA). (B) Myocardial 3-NT and 4-HNE content. (C) Representative images of cardiac 3-NT immunohistochemistry. Magnification: 200×. *P < 0.05 versus CTL; #P < 0.05 versus EAM.

Figure 5.

Effects of CBD on myocardial fibrotic remodeling induced by EAM. (A) Representative images of Masson trichrome–stained LV myocardial sections. Magnification: 100×. (B) LV mRNA expression of collagen 1α (Col1a). (C) Representative images of Sirius red–stained LV myocardium sections. Magnification: 100×. (D) Quantification of Sirius red positive area in LV myocardium. *P < 0.05 versus CTL; #P < 0.05 versus EAM.

Figure 6.

Effects of CBD on EAM-associated myocardial dysfunction and loss of body weight. (A) Classic indices of left ventricular systolic (ejection fraction, cardiac output, dP/dtmax) and diastolic (left ventricular end-diastolic pressure [LVEDP], TauW) and load-independent contractility (ESPVR), PRSW and diastolic stiffness (slope of EDPVR) parameters. (B) Representative pressure-volume loops of CFA, EAM and EAM + CBD groups. (C) Graph of body weight changes during the study course. *P < 0.05 versus CTL; #P < 0.05 versus EAM.

Figure 7.

Summary flowchart of the effects of CBD in EAM. The schematic diagram shows the pathophysiology of EAM and the potential sites of a beneficial intervention with CBD treatment.