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      Different Factors Affecting Human ANP Amyloid Aggregation and Their Implications in Congestive Heart Failure

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          Abstract

          Aims

          Atrial Natriuretic Peptide (ANP)-containing amyloid is frequently found in the elderly heart. No data exist regarding ANP aggregation process and its link to pathologies. Our aims were: i) to experimentally prove the presumptive association of Congestive Heart Failure (CHF) and Isolated Atrial Amyloidosis (IAA); ii) to characterize ANP aggregation, thereby elucidating IAA implication in the CHF pathogenesis.

          Methods and Results

          A significant prevalence (85%) of IAA was immunohistochemically proven ex vivo in biopsies from CHF patients. We investigated in vitro (using Congo Red, Thioflavin T, SDS-PAGE, transmission electron microscopy, infrared spectroscopy) ANP fibrillogenesis, starting from α-ANP as well as the ability of dimeric β-ANP to promote amyloid formation. Different conditions were adopted, including those reproducing β-ANP prevalence in CHF. Our results defined the uncommon rapidity of α-ANP self-assembly at acidic pH supporting the hypothesis that such aggregates constitute the onset of a fibrillization process subsequently proceeding at physiological pH. Interestingly, CHF-like conditions induced the production of the most stable and time-resistant ANP fibrils suggesting that CHF affected people may be prone to develop IAA.

          Conclusions

          We established a link between IAA and CHF by ex vivo examination and assessed that β-ANP is, in vitro, the seed of ANP fibrils. Our results indicate that β-ANP plays a crucial role in ANP amyloid deposition under physiopathological CHF conditions. Overall, our findings indicate that early IAA-related ANP deposition may occur in CHF and suggest that these latter patients should be monitored for the development of cardiac amyloidosis.

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          Most cited references32

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          Quantification of beta-sheet amyloid fibril structures with thioflavin T.

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            Myocardial structure and function differ in systolic and diastolic heart failure.

            To support the clinical distinction between systolic heart failure (SHF) and diastolic heart failure (DHF), left ventricular (LV) myocardial structure and function were compared in LV endomyocardial biopsy samples of patients with systolic and diastolic heart failure. Patients hospitalized for worsening heart failure were classified as having SHF (n=22; LV ejection fraction (EF) 34+/-2%) or DHF (n=22; LVEF 62+/-2%). No patient had coronary artery disease or biopsy evidence of infiltrative or inflammatory myocardial disease. More DHF patients had a history of arterial hypertension and were obese. Biopsy samples were analyzed with histomorphometry and electron microscopy. Single cardiomyocytes were isolated from the samples, stretched to a sarcomere length of 2.2 microm to measure passive force (Fpassive), and activated with calcium-containing solutions to measure total force. Cardiomyocyte diameter was higher in DHF (20.3+/-0.6 versus 15.1+/-0.4 microm, P<0.001), but collagen volume fraction was equally elevated. Myofibrillar density was lower in SHF (36+/-2% versus 46+/-2%, P<0.001). Cardiomyocytes of DHF patients had higher Fpassive (7.1+/-0.6 versus 5.3+/-0.3 kN/m2; P<0.01), but their total force was comparable. After administration of protein kinase A to the cardiomyocytes, the drop in Fpassive was larger (P<0.01) in DHF than in SHF. LV myocardial structure and function differ in SHF and DHF because of distinct cardiomyocyte abnormalities. These findings support the clinical separation of heart failure patients into SHF and DHF phenotypes.
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              Quantitative evaluation of congo red binding to amyloid-like proteins with a beta-pleated sheet conformation.

              The binding of Congo red to several purified amyloid-like peptides having a beta-pleated sheet conformation was quantitatively examined. Congo red binds preferentially to the beta-pleated sheet conformation of both insulin fibrils and poly-L-lysine. Congo red does not bind nearly so well to poly-L-serine or polyglycine, despite the fact that these peptides also have a beta-pleated sheet conformation. Binding to insulin fibrils was saturable with an apparent Bmax of 2 moles of Congo red per mole of insulin fibrils and an apparent KD of 1.75 x 10(-7) M. Binding to beta-poly-L-lysine was similar but had a much higher apparent Bmax of 43. Binding of Congo red to beta-poly-L-lysine was pH dependent and appeared to be determined by the number of protonated lysine residues in the 250 amino acid peptide. We present a new hypothesis in which Congo red binds to amyloid-like proteins via bonds between the two negatively charged sulfonic acid groups of Congo red and two positively charged amino acid residues of two separate protein molecules which are properly oriented by virtue of the beta-pleated sheet conformation of the peptide backbone.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                26 July 2011
                : 6
                : 7
                : e21870
                Affiliations
                [1 ]Dipartimento di Biotecnologie, Università degli Studi di Siena, Siena, Italy
                [2 ]Dipartimento di Biologia Evolutiva, Università degli Studi di Siena, Siena, Italy
                [3 ]Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy
                [4 ]Dipartimento di Medicina Clinica e Scienze Immunologiche, Università degli Studi di Siena, Siena, Italy
                [5 ]Dipartimento di Patologia Umana e Oncologia, Università degli Studi di Siena, Siena, Italy
                Université Joseph Fourier, France
                Author notes

                Conceived and designed the experiments: LM GB LG A. Santucci PL AM. Performed the experiments: LM LG A. Spreafico MC DB ML EP. Analyzed the data: LM LG GB DB EP A. Santucci PT A. Spreafico AM. Contributed reagents/materials/analysis tools: PT A. Santucci A. Spreafico AM PL. Wrote the paper: LM GB A. Santucci.

                Article
                PONE-D-11-05399
                10.1371/journal.pone.0021870
                3144199
                21814559
                b6cdfbb8-a1b4-4692-83dc-5f480ec24204
                Millucci et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 22 March 2011
                : 8 June 2011
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Biochemistry
                Proteins
                Protein Structure
                Biophysics
                Protein Folding
                Medicine
                Cardiovascular
                Geriatric Cardiology
                Heart Failure
                Geriatrics

                Uncategorized
                Uncategorized

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