Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy.

BACKGROUND: Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer's disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies 'beyond the brain'. This study aims to establish tau's putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). METHODS AND RESULTS: A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. CONCLUSION: The study presents new mechanistic evidence and potential treatment for the brain-heart tauopathy axis in myocardial and brain degenerative diseases and ageing.

Trimethylamine-N-oxide is associated with cardiovascular mortality and vascular brain lesions in patients with atrial fibrillation.

OBJECTIVE: Trimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation. METHODS: Baseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1-Q3: 3.0-5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors. RESULTS: Subjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m2 (35.6-62.5) vs 67.3 mL/min/1.73 m2 (57.8-78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01). CONCLUSIONS: High levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation. TRIAL REGISTRATION NUMBER: NCT02105844.

The long and winding road to target protein misfolding in cardiovascular diseases.

BACKGROUND: In the last decades, cardiovascular diseases (CVD) have remained the first leading cause of mortality and morbidity in the world. Although several therapeutic approaches have been introduced in the past, the development of novel treatments remains an important research goal, which is hampered by the lack of understanding of key mechanisms and targets. Emerging evidences in recent years indicate the involvement of misfolded proteins aggregation and the derailment of protein quality control in the pathogenesis of cardiovascular diseases. Several potential interventions targeting protein quality control have been translated from the bench to the bedside to effectively employ the misfolded proteins as promising therapeutic targets for cardiac diseases, but with trivial results. DESIGN: In this review, we describe the recent progresses in preclinical and clinical studies of protein misfolding and compromised protein quality control by selecting and reporting studies focusing on cardiovascular diseases including cardiomyopathies, cardiac amyloidosis, atherosclerosis, atrial fibrillation and thrombosis. RESULTS: In preclinical models, modulators of several molecular targets (eg heat shock proteins, unfolded protein response, ubiquitin protein system, autophagy and histone deacetylases) have been tested in various conditions with promising results although lacking an adequate transition towards clinical setting. CONCLUSIONS: At present, no therapeutic strategies have been reported to attenuate proteotoxicity in patients with CVD due to a lack of specific biomarkers for pinpointing upstream events in protein folding defects at a subclinical stage of the diseases requiring an intensive collaboration between basic scientists and clinicians.

Proteomic analysis of monkey kidney LLC-MK2 cells infected with a Thai strain Zika virus.

Zika virus (ZIKV) has been endemic in Southeast Asian countries for several years, but the presence of the virus has not been associated with significant outbreaks of infection unlike other countries around the world where the Asian lineage ZIKV was introduced recently. However, few studies have been undertaken using the endemic virus. The Thai isolate was shown to have a similar tissue tropism to an African isolate of ZIKV, albeit that the Thai isolate infected cells at a lower level as compared to the African isolate. To further understand the pathogenesis of the Thai isolate, a 2D-gel proteomic analysis was undertaken of ZIKV infected LLC-MK2 cells. Seven proteins (superoxide dismutase [Mn], peroxiredoxin 2, ATP synthase subunit alpha, annexin A5 and annexin A1, carnitine o-palmitoyltransferase 2 and cytoskeleton-associated protein 2) were identified as differentially regulated. Of four proteins selected for validation, three (superoxide dismutase [Mn], peroxiredoxin 2, ATP synthase subunit alpha, and annexin A1) were shown to be differentially regulated at both the transcriptional and translational levels. The proteins identified were primarily involved in energy production both directly, and indirectly through mediation of autophagy, as well as in the response to oxidative stress, possibly occurring as a consequence of increased energy production. This study provides further new information on the pathogenesis of ZIKV.

Evaluation of Silver Ion-Releasing Scaffolds in a 3D Coculture System of MRSA and Human Adipose-Derived Stem Cells for Their Potential Use in Treatment or Prevention of Osteomyelitis.

Bone infection, also called osteomyelitis, can result when bacteria invade a bone. Treatment of osteomyelitis usually requires surgical debridement and prolonged antimicrobial therapy. The rising incidence of infection with multidrug-resistant bacteria, in particular methicillin-resistant staphylococcus aureus (MRSA), however, limits the antimicrobial treatment options available. Silver is well known for its antimicrobial properties and is highly toxic to a wide range of microorganisms. We previously reported our development of biocompatible, biodegradable, nanofibrous scaffolds that released silver ions in a controlled manner. The objective of this study was to determine the efficacy of these scaffolds in treating or preventing osteomyelitis. To achieve this objective, antimicrobial efficacy was determined using a 3D coculture system of human adipose-derived stem cells (hASC) and MRSA. Human ASC were seeded on the scaffolds and induced to undergo osteogenic differentiation in both the absence and presence of MRSA. Our results indicated that the silver ion-releasing scaffolds not only inhibited biofilm formation, but also supported osteogenesis of hASC. Our findings suggest that these biocompatible, degradable, silver ion-releasing scaffolds can be used at an infection site to treat osteomyelitis and/or to coat bone implants as a preventative measure against infection postsurgery.