Androgen receptor regulates cardiac fibrosis in mice with experimental autoimmune myocarditis by increasing microRNA-125b expression.

Cardiac fibrosis is an important cardiac remodeling event in the development of inflammation dilated cardiomyopathy （iDCM）. We have previously observed that degradation enhancer of androgen receptor (ASC-J9®) could improve cardiac inflammation and fibrosis. Using Primary CFs, we demonstrated that ASC-J9® attenuates the expression of miR-125b, which subsequently inhibits the generation of collagen. In contrast, overexpressed AR in CFs induced collagen production, increases mir-125b.We also found that inhibition of miR-125b attenuates fibrosis which induced by the overexpression of AR. Our results indentify the functional role for AR as a regulator of cardiac fibrosis due to myocarditis and further show that AR exerts its effect by increasing microRNA-125b expression. Treatment with degradation enhancer of AR limits cardiac fibrosis in iDCM, thereby providing potentially a therapeutic approach for patients with iDCM.

Vaccination with 73kDa recombinant heavy chain myosin generates high level of protection against Brugia malayi challenge in jird and mastomys models.

We have earlier reported identification, expression and purification of a 2.0kb cDNA clone coding for Brugia malayi heavy chain myosin which exhibited strong immuno-reactivity with bancroftian sera from endemic normal (EN) human subjects which are considered to be putatively immune. In the present study, immunoprophylactic characterization of B. malayi recombinant myosin was carried out in rodent models and the protective efficacy was evaluated by assessing the microfilarial burden and adult worm counts in vaccinated host after an infective larval challenge. Data indicates that immunization resulted in to a significant reduction in microfilarial burden (approximately 76%) and adult worm establishment (54-58%), accompanied with embryostatic effect (70-75%) in both the animal models. The findings suggest that immune-protection by recombinant myosin was conferred through both humoral and cellular arms of immunity as indicated by an increased antibody titer with predominance of IgG2a and IgG2b isotypes along with elevated level of IgG1 apart from significant proliferation of lymphocytes, increased nitric oxide production and profound adherence of splenocytes causing cytotoxicity to microfilariae and infective larvae. The present study indicates that the recombinant B. malayi myosin is a promising vaccine candidate against human lymphatic filarial infection.

MyD88 signaling controls autoimmune myocarditis induction.

BACKGROUND: Experimental autoimmune myocarditis (EAM) is a CD4+ T-cell-mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known. METHODS AND RESULTS: In contrast to control littermates, MyD88(-/-) mice were protected from myocarditis after immunization with alpha-myosin heavy chain-derived peptide (MyHC-alpha) and complete Freund's adjuvant. Disease resistance of MyD88(-/-) mice resulted from impaired expansion of heart-specific CD4+ T cells after immunization. Intrinsic defects of MyD88(-/-) CD4+ T cells were excluded. In contrast, MyD88(-/-) but not MyD88(+/+) primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4+ T cells. This defect mainly resulted from the inability of MyD88(-/-) DCs to release tumor necrosis factor-alpha. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-alpha-loaded MyD88(+/+) DCs that fully restored T-cell expansion and myocarditis in MyD88(-/-) mice. CONCLUSIONS: Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.

Forced expression of alpha-myosin heavy chain in the rabbit ventricle results in cardioprotection under cardiomyopathic conditions.

BACKGROUND: The biochemical differences between the 2 mammalian cardiac myosin heavy chains (MHCs), alpha-MHC and beta-MHC, are well described, but the physiological consequences of basal isoform expression and isoform shifts in response to altered cardiac load are not clearly understood. Mature human ventricle contains primarily the beta-MHC isoform. However, the alpha-MHC isoform can be detected in healthy human ventricle and appears to be significantly downregulated in failing hearts. The unique biochemical properties of the alpha-MHC isoform might offer functional advantages in a failing heart that is expressing only the beta-MHC isoform. This hypothesis cannot be tested in mice or rats because both species express alpha-MHC as the predominant isoform. METHODS AND RESULTS: To test the effects of persistent alpha-MHC expression on the background of beta-MHC, we made transgenic (TG) rabbits that expressed rabbit alpha-MHC cDNA in the ventricle so that the endogenous myosin was partially replaced by the transgenically encoded species. Molecular, histological, and functional analyses showed no significant baseline effects in the TG rabbits compared with nontransgenic (NTG) littermates. To determine whether alpha-MHC expression afforded any advantages to stressed myocardium, a cohort of TG and NTG rabbits was subjected to rapid ventricular pacing. Although both the TG and NTG rabbits developed dilated cardiomyopathy, the TG rabbits had a higher shortening fraction, less septal thinning, and more normal +/-dP/dt than paced NTG rabbits. CONCLUSIONS: Transgenic expression of alpha-MHC does not have any apparent detrimental effects under basal conditions and is cardioprotective in experimental tachycardia-induced cardiomyopathy.

Cardiac myosin autoimmunity in acute Chagas' heart disease.

Infection with Trypanosoma cruzi, the agent of Chagas' disease, may induce antibodies and T cells reactive with self antigens (autoimmunity). Because autoimmunity is generally thought to develop during the chronic phase of infection, one hypothesis is that autoimmunity develops only after long-term, low-level stimulation of self-reactive cells. However, preliminary reports suggest that autoimmunity may begin during acute T. cruzi infection. The goal of the present study was to investigate whether cardiac autoimmunity could be observed during acute T. cruzi infection. A/J mice infected with the Brazil strain of T. cruzi for 21 days developed severe myocarditis, accompanied by humoral and cellular autoimmunity. Specifically, T. cruzi infection induced immunoglobulin G (IgG) autoantibodies and delayed type hypersensitivity (DTH) to cardiac myosin. This autoimmunity resembles that which develops in A/J mice immunized with myosin in complete Freund's adjuvant in that myosin-specific antibodies and DTH responses both develop by 21 days postinfection or postimmunization. While the levels of myosin IgG in T. cruzi-infected mice were slightly lower than those in myosin-immunized mice, the magnitude of myosin DTH in the two groups was statistically equivalent. In contrast, C57BL/6 mice, which are resistant to myosin-induced myocarditis and its associated autoimmunity, developed undetectable or low levels of myosin IgG and did not exhibit myosin DTH or myocarditis upon T. cruzi infection. Therefore, humoral and cellular cardiac autoimmunity can develop during acute T. cruzi infection in the genetically susceptible host.