8 research outputs found
MYOCARDIAL MICRORNAS AND ION CHANNELS ARE DOWNREGULATED IN HEART FAILURE PATIENTS WITH SEVERE VENTRICULAR TACHYARRHYTHMIAS
Serum protein profile in systemic-onset juvenile idiopathic arthritis differentiates response versus nonresponse to therapy
Systemic-onset juvenile idiopathic arthritis (SJIA) is a disease of unknown etiology with an unpredictable response to treatment. We examined two groups of patients to determine whether there are serum protein profiles reflective of active disease and predictive of response to therapy. The first group (n = 8) responded to conventional therapy. The second group (n = 15) responded to an experimental antibody to the IL-6 receptor (MRA). Paired sera from each patient were analyzed before and after treatment, using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Despite the small number of patients, highly significant and consistent differences were observed before and after response to therapy in all patients. Of 282 spectral peaks identified, 23 had mean signal intensities significantly different (P < 0.001) before treatment and after response to treatment. The majority of these differences were observed regardless of whether patients responded to conventional therapy or to MRA. These peaks represent potential biomarkers of active disease. One such peak was identified as serum amyloid A, a known acute-phase reactant in SJIA, validating the SELDI-TOF MS platform as a useful technology in this context. Finally, profiles from serum samples obtained at the time of active disease were compared between the two patient groups. Nine peaks had mean signal intensities significantly different (P < 0.001) between active disease in patients who responded to conventional therapy and in patients who failed to respond, suggesting a possible profile predictive of response. Collectively, these data demonstrate the presence of serum proteomic profiles in SJIA that are reflective of active disease and suggest the feasibility of using the SELDI-TOF MS platform used as a tool for proteomic profiling and discovery of novel biomarkers in autoimmune diseases
MYOCARDIAL MICRORNAS AND ION CHANNELS ARE DOWNREGULATED IN HEART FAILURE PATIENTS WITH SEVERE VENTRICULAR TACHYARRHYTHMIAS
Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-α
Dysregulated Autophagy and Sarcomere Dysfunction in Patients With Heart Failure With CoâOccurrence of P63A and P380S BAG3 Variants
Background Mutations to the coâchaperone protein BAG3 (Bâcell lymphomaâ2âassociated athanogeneâ3) are a leading cause of dilated cardiomyopathy (DCM). These mutations often impact the Câterminal BAG domain (residues 420â499), which regulates heat shock protein 70âdependent protein turnover via autophagy. While mutations in other regions are less common, previous studies in patients with DCM found that coâoccurrence of 2 BAG3 variants (P63A, P380S) led to worse prognosis. However, the underlying mechanism for dysfunction is not fully understood. Methods and Results In this study, we used proteomics, Western blots, and myofilament functional assays on left ventricular tissue from patients with nonfailing, DCM, and DCM with BAG363/380 to determine how these mutations impact protein quality control and cardiomyocyte contractile function. We found dysregulated autophagy and increased protein ubiquitination in patients with BAG363/380 compared with nonfailing and DCM, suggesting impaired protein turnover. Expression and myofilament localization of BAG3âbinding proteins were also uniquely altered in the BAG3,63/380 including abolished localization of the small heat shock protein CRYAB (alphaâcrystallin B chain) to the sarcomere. To determine whether these variants impacted sarcomere function, we used cardiomyocyte forceâcalcium assays and found reduced maximal calciumâactivated force in DCM and BAG363/380. Interestingly, myofilament calcium sensitivity was increased in DCM but not with BAG363/380, which was not explained by differences in troponin I phosphorylation. Conclusions Together, our data support that the diseaseâenhancing mechanism for BAG3 variants outside of the BAG domain is through disrupted protein turnover leading to compromised sarcomere function. These findings suggest a shared mechanism of disease among pathogenic BAG3 variants, regardless of location