ABSTRACT
Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGFß-Smad2/3 signaling. Targeting the ubiquitous TGFß leads to cellular homeostasis deregulation with adverse consequences. We previously showed the anti-fibrotic effects upon downregulation of 90-kDa heat shock protein (Hsp90), a chaperone that associates to the TGFß signaling cascade. In the present study, we use a fluorescent-labeled Hsp90 protein inhibitor (CTPR390-488) with specific Hsp90 binding properties to reduce myocardial pro-fibrotic events in vitro and in vivo. The mechanism of action involves the disruption of TGFßRI-Hsp90 complex, resulting in a decrease in TGFß signaling and reduction in extracellular matrix collagen. In vivo, decreased myocardial collagen deposition was observed upon CTPR390-488 treatment in a pro-fibrotic mouse model. This is the first study demonstrating the ability of an engineered Hsp90 protein inhibitor to block collagen expression, reduce the motility of myocardial TGFß-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Myocardium/metabolism , Transforming Growth Factor beta/metabolism , Angiotensin II/metabolism , Angiotensin II/pharmacology , Animals , Cell Survival/drug effects , Cells, Cultured , Collagen/metabolism , Disease Models, Animal , Extracellular Matrix/metabolism , Fibroblasts/metabolism , Fibroblasts/ultrastructure , Fibrosis , Fluorescent Antibody Technique , HSP90 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/genetics , Mice , Mice, Knockout , Microscopy, Confocal , Models, Molecular , Myocardium/pathology , Peptides/chemistry , Peptides/pharmacology , Protein Binding , Protein Conformation , Quantitative Structure-Activity Relationship , Signal Transduction/drug effects , Transforming Growth Factor beta/pharmacologyABSTRACT
OBJECTIVE: Evaluate the efficacy of acupuncture associated with physiotherapy for patients with painful shoulder. METHODS: In a multicentre controlled randomized study, participants were recruited with a clinical diagnosis of unilateral subacromial syndrome from six rehabilitation medicine departments belonging to the Public Health System in two Spanish regions. All participants received 15 sessions of physiotherapy during the 3 weeks that the treatment lasted and were randomized to additionally receive, once a week, acupuncture or mock TENS (transcutaneous electrical nerve stimulation). The primary outcome measure was the change in the Constant-Murley Score (CMS) for functional assessment of the shoulder, at 4 weeks after randomization. This study is registered as an International Standard Randomized Controlled Trial, number ISRCTN28687220. RESULTS: A total of 425 patients were recruited. The mean score (s.d.) on the CMS had increased by 16.6 (15.6) points among the acupuncture group, compared with 10.6 (13.5) points in the control group, and the mean difference between the two groups was statistically significant (6.0 points; 95% CI 3.2, 8.8 points; P < 0.001). By the end of the treatment, 53% of the patients in the acupuncture group had decreased their consumption of analgesics, compared with a corresponding 30% among the control group (P < 0.001). CONCLUSIONS: Single-point acupuncture in association with physiotherapy improves shoulder function and alleviates pain, compared with physiotherapy as the sole treatment. This improvement is accompanied by a reduction in the consumption of analgesic medicaments.
