1,721,133 research outputs found
Protein unfolding in cardiomyopathies.
No full textFor many years, protein misfolding was the basis for biochemical and biophysical studies in vitro or in microorganisms such as yeast. Recently, clinically related studies are merging the evidence collected from microorganisms with human diseases. Thus, a growing body of evidence is accumulating that identifies defects in protein folding or protein degradation as pathogenetic hallmarks for many disease entities predominantly of late onset, including cardiomyopathies and heart failure. Dissecting the pathogenetic pathways opens new opportunities for therapy aimed to re-equilibrate the folding capacities. The development of chemical and pharmacologic chaperones has helped to understand the mechanisms of some aspects of protein misfolding and may find new applications to direct target-specific therapy. Further understanding of the mechanisms of protein formation and its defects will address the important aspects of modern medicine of directing early diagnosis and prevention
Protein post-translational modifications and misfolding: new concepts in heart failure.
No full textA new concept in the field of heart-failure (HF) research points to a role of misfolded proteins, forming preamyloid oligomers (PAOs), in cardiac toxicity. This is largely based on few studies
reporting the presence of PAOs, similar to those observed in neurodegenerative diseases, in experimental and human HF. As the majority of proteinopathies are sporadic in nature, protein post-translational modifications (PTMs) likely play a major role in this growing class of
diseases. In fact, PTMs are known regulators of protein folding and of the formation of amyloid species in well-established proteinopathies. Proteomics has been instrumental in identifying
both chemical and enzymatic PTMs, with a potential impact on protein mis-/folding. Here we provide the basics on how proteins fold along with a few examples of PTMs known to modulate
protein misfolding and aggregation, with particular focus on the heart. Due to its innovative content and the growing awareness of the toxicity of misfolded proteins, an “Alzheimer’s theory of HF” is timely. Moreover, the continuous innovations in proteomic technologies will help pinpoint PTMs that could contribute to the process. This nuptial between biology and technology could greatly assist in identifying biomarkers with increased specificity as well as more effective therapies
Intracellular devastation in heart failure
No full textEnd-stage heart failure is characterized by a
number of abnormalities at the cellular level, which include
changes in excitation–contraction coupling, alterations in
contractile proteins and activation/deactivation of signaling
pathways. Even though many of these changes are adaptive
to the high workload and stress in heart failure, a signifi-
cant number of these alterations are deeply deleterious to
the cardiac cell. In this article, we will review the changes
in calcium cycling that occur in myopathic hearts and how
they can be effectively targeted. We will also focus on
protein misfolding in the setting of cardiac dysfunctio
The More We Learn, The Less We Know: A Novel Cardiac Mechanism of Brain Damage
No full textNot availabl
Current and Future Circulating Biomarkers for Cardiac Amyloidosis
No full textCardiac amyloidosis (CA) comprises a heterogeneous group of medical conditions affecting the myocardium. It presents with proteinaceous infiltration with variable degrees of severity, prevalence and evolution. Despite this heterogeneity, erroneous protein folding is the common pathophysiologic process, yielding the formation of a single misfolded protein (monomer) that progressively evolves and ultimately forms amyloid fibers. Additionally, by seeding out from the organs of origin, intermediates called oligomers metastasize and restart the process. Such self-echoing behavior makes the secondary affected organs as important as the primary ones. Unfortunately, CA can be clinically challenging and only suggestive in a late stage of its natural history, leaving a narrow therapeutic time window available. In light of the evolutionary nature of amyloidosis, here, we propose a new classification of the currently used biomarkers based on time stages with different specificity and applicability across CA subtypes. Early markers (free light chains, serum amyloid A, β2-microglobulin, osteopontin and osteoprotegerin) can be employed for disease detection. Intermediate markers [soluble suppression of tumorigenicity 2 (sST-2), midregional proadrenomedullin (MR-proADM), von Willebrand factor (vWF), hepatocyte growth factor (HGF), matrix metalloproteinases (MMPs) and tissue inhibitor metalloproteinases (TIMPs)] can provide information on the biological mechanisms of myocardial damage. As in heart failure, late-stage biomarkers (troponins and natriuretic peptides) can help clinicians with prognosis and therapeutic response evaluation in CA. Such findings have generated a remarkable foundation for our current knowledge on CA. Nevertheless, we envision a future class of biomarkers targeted at upstream events capable of detecting folding defects, which will ultimately expand the therapeutic window
From Current to Future Circulating Biomarkers for Cardiac Amyloidosis
No full textCardiac amyloidosis (CA) comprises a heterogeneous group of medical conditions affecting the myocardium. It presents with proteinaceous infiltration with variable degrees of severity, prevalence and evolution. Despite this heterogeneity, erroneous protein folding is the common pathophysiologic process, yielding the formation of a single misfolded protein (monomer) that progressively evolves and ultimately forms amyloid fibers. Additionally, by seeding out from the organs of origin, intermediates called oligomers metastasize and restart the process. Such self-echoing behavior makes the secondary affected organs as important as the primary ones. Unfortunately, CA can be clinically challenging and only suggestive in a late stage of its natural history, leaving a narrow therapeutic time window available. In light of the evolutionary nature of amyloidosis, here, we propose a new classification of the currently used biomarkers based on time stages with different specificity and applicability across CA subtypes. Early markers (free light chains, serum amyloid A, β2-microglobulin, osteopontin and osteoprotegerin) can be employed for disease detection. Intermediate markers [soluble suppression of tumorigenicity 2 (sST-2), midregional proadrenomedullin (MR-proADM), von Willebrand factor (vWF), hepatocyte growth factor (HGF), matrix metalloproteinases (MMPs) and tissue inhibitor metalloproteinases (TIMPs)] can provide information on the biological mechanisms of myocardial damage. As in heart failure, late-stage biomarkers (troponins and natriuretic peptides) can help clinicians with prognosis and therapeutic response evaluation in CA. Such findings have generated a remarkable foundation for our current knowledge on CA. Nevertheless, we envision a future class of biomarkers targeted at upstream events capable of detecting folding defects, which will ultimately expand the therapeutic window
Insights from Second-Line Treatments for Idiopathic Dilated Cardiomyopathy
No full textBackground: Dilated cardiomyopathy (DCM) is an independent nosographic entity characterized by left ventricular dilatation and contractile dysfunction leading to heart failure (HF). The idiopathic form of DCM (iDCM) occurs in the absence of coronaropathy or other known causes of DCM. Despite being different from other forms of HF for demographic, clinical, and prognostic features, its current pharmacological treatment does not significantly diverge. Methods: In this study we performed a Pubmed library search for placebo-controlled clinical investigations and a post-hoc analysis recruiting iDCM from 1985 to 2016. We searched for second-line pharmacologic treatments to reconsider drugs for iDCM management and pinpoint pathological mechanisms. Results: We found 33 clinical studies recruiting a total of 3392 patients of various durations and sizes, as well as studies that tested different drug classes (statins, pentoxifylline, inotropes). A metanalysis was unfeasible, although a statistical significance for changes upon treatment for molecular results, morphofunctional parameters, and clinical endpoints was reported. Statins appeared to be beneficial in light of their pleiotropic effects; inotropes might be tolerated more for longer times in iDCM compared to ischemic patients. General anti-inflammatory therapies do not significantly improve outcomes. Metabolic and growth modulation remain appealing fields to be investigated. Conclusions: The evaluation of drug effectiveness based on direct clinical benefit is an inductive method providing evidence-based insights. This backward approach sheds light on putative and underestimated pathologic mechanisms and thus therapeutic targets for iDCM management
Circular quiver gauge theories, isomonodromic deformations and WN fermions on the torus
Full text linkWe study the relation between class S theories on punctured tori and isomonodromic deformations of flat SL(N) connections on the two-dimensional torus with punctures. Turning on the self-dual Ω -background corresponds to a deautonomization of the Seiberg–Witten integrable system which implies a specific time dependence in its Hamiltonians. We show that the corresponding τ-function is proportional to the dual gauge theory partition function, the proportionality factor being a nontrivial function of the solution of the deautonomized Seiberg–Witten integrable system. This is obtained by mapping the isomonodromic deformation problem to WN free fermion correlators on the torus
Interaction between increased SERCA2a activity and beta -adrenoceptor stimulation in adult rabbit myocytes
No full textSarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a overexpression and phospholamban depletion have been shown to have beneficial effects on contractility in heart failure. However, the high sympathetic tone during development of failure may interact with increases in SERCA2a activity in potentially deleterious ways. We used adenoviral vectors to overexpress SERCA2a or partially downregulate phospholamban in adult rabbit ventricular myocytes in culture and studied the responses of these cells to beta-adrenoceptor stimulation. SERCA2a overexpression and phospholamban depletion had quantitatively similar effects on basal contraction amplitude and in accelerating relaxation. Increasing SERCA2a activity by either strategy had little effect on the increase in contraction amplitude or incidence of arrhythmias with increasing isoproterenol. Maximum acceleration of relaxation by beta-adrenoceptor stimulation was similar to that produced by SERCA2a overexpression. Isoproterenol treatment of SERCA2a-overexpressing or phospholamban-deficient myocytes produced a further modest decrease in relaxation time, with similar final values in both groups. We find no evidence for Ca(2+) overload induced by SERCA2a overexpression alone or in combination with catecholamines
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