A review of the amyloidoses that infiltrate the heart

McCarthy, Robert E.; Kasper, Edward K.

doi:10.1002/clc.4960210804

Cited by 62 publications

(45 citation statements)

References 39 publications

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“…These deposits, which now are known to include intracellular aggregates or inclusions as well, can be stained with the amyloidphilic dyes such as Congo red, and many of the misfolded proteins responsible for or present in the aggregates are known (42). Both hereditary and nonhereditary forms of systemic amyloidoses have been identified and can have diverse effects on cardiac function, resulting in dilative cardiomyopathy, restrictive cardiomyopathy, or diastolic dysfunction (43)(44)(45)(46). Accumulation and aggregation of misfolded proteins is a hallmark of the amyloidoses, which include Alzheimer's disease (47), Huntington's disease (48), Parkinson's disease (25), and the spongiform encephalopathies (49).…”

Section: Discussionmentioning

confidence: 99%

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Sanbe

Osińska

Saffitz

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

271

321

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An R120G missense mutation in the small heat shock protein ␣-B-crystallin (CryAB R120G ) causes desmin-related cardiomyopathy (DRM). DRM is characterized by the formation of aggregates containing CryAB and desmin, and it can be recapitulated in transgenic mice by cardiac-specific expression of the mutant protein. In this article, we show that expression of CryAB R120G leads to the formation of electron-dense bodies characteristic of the DRMs and identify these bodies as aggresomes, which are characteristic of the neurodegenerative diseases. Cardiomyocytes transfected with adenovirus containing CryAB R120G establish the necessity and sufficiency of CryAB R120G expression for aggresome formation. The commonality of these aggresomes with oligomeric protein aggregates found in the amyloid-related degenerative diseases was corroborated by the presence of high levels of amyloid oligomers that may represent a primary toxic species in the amyloid diseases. These oligomeric amyloid intermediates are present also in cardiomyocytes derived from many human dilated and hypertrophic cardiomyopathies.H uman heart failure is the leading cause of death in the developed world, and it represents a final common endpoint for several disease entities, including hypertension, coronary artery disease, and the cardiomyopathies (1, 2). A lack of pathogenic commonality is underscored by the large number of mutations in different classes of cardiac proteins that have been linked to dilated and hypertrophic cardiomyopathy (HCM) (3). Mutations in the cytoskeletal and associated proteins can be causative because these proteins function in structural, sensor, and signaling roles in the normal and diseased cardiomyocyte (4). For example, up-regulation of the intermediate filament protein desmin occurs in cardiac disorders such as cardiac hypertrophy and congestive heart failure (CHF) (5), and desmin mutations are associated with desmin-related cardiomyopathy (DRM) and idiopathic dilated cardiomyopathy (6, 7). Mutations in other proteins also have been associated with the DRMs, and genetic evidence linking an R120G mutation in ␣-B-crystallin (CryAB, CryAB R120G ) to human DRM (8) prompted a series of experiments in which we showed that cardiac-restricted transgenic (TG) expression of CryAB R120G was sufficient to cause heart failure in a mouse model (9). Although up-regulation of CryAB is associated with disease states including DRM, its synthesis probably represents a general cellular response to stress because CryAB has chaperone-like activity. Indeed, CryAB, which binds to both desmin and cytoplasmic actin, probably participates normally as a chaperone in intermediate filament formation and maintenance in the heart.The ␣-crystallins (␣-A and ␣-B) were of interest initially as major structural proteins present in the lens of the vertebrate eye. However, the discovery that they were related to the small heat shock proteins (hsps) in Drosophila (10) prompted reevaluation of their broader role(s), and it is now known that CryAB belongs to the sma...

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Section: Discussionmentioning

confidence: 99%

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Sanbe

Osińska

Saffitz

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

271

321

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“…Amyloid deposits in the ageing heart are a common finding at autopsy (McCarthy & Kasper 1998); in the majority of cases, it is an age-related cardiac amyloidosis that can be separated into two groups. The first one is a systemic form, known as senile systemic amyloidosis (SSA) (Sletten et al 1980, Pitkanen et al 1984, in which the protein fibril is derived from transthyretin (TTR); SSA mainly affects cardiac ventricles, although other organs are also involved.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, these human proteins are known to bind A (Koudinov et al 1994, Bohrmann et al 1999, Tsuzuki et al 2000 or ANP (present paper), probably preventing fibrillar aggregation. At the same time, all these factors exhibit the intrinsic potential to form amyloid deposits (Sletten et al 1980, Pitkanen et al 1984, McCarthy & Kasper 1998, Bergstrom et al 2001, Andreola et al 2003.…”

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confidence: 99%

Multiple plasma proteins control atrial natriuretic peptide (ANP) aggregation

Torricelli

Capurro²,

Santucci³

et al. 2004

Journal of Molecular Endocrinology

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We have recently demonstrated that human -atrial natriuretic peptide ( -hANP), an amyloidogenic peptide responsible for isolated atrial amyloidosis, binds to a dimeric form of apo A-I belonging to small high-density lipoproteins (HDL). This binding phenomenon is considered a protective mechanism since it inhibits or strongly reduces the ANP aggregation process. The observation that plasma exhibits at least four times greater amyloid inhibitory activity than HDL prompted us to determine whether small HDL are the only ANP plasma-binding factors. After incubation of whole plasma with labelled ANP, the macromolecular complexes were subjected to two-dimensional gel electrophoresis followed by autoradiography. The results presented here provide novel evidence of additional binding proteins, in addition to apo A-I dimer, able to bind ANP in vitro and to prevent its aggregation. The mass spectrometry analysis of the radioactive spots identified them as albumin, -1 antitrypsin, orosomucoid and apo A-IV-TTR complex. The putative impact of these findings in the amyloidogenic/antiamyloidogenic peptides network is discussed.

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“…This process also occurs very slowly under physiological conditions (23)(24)(25). Senile systemic amyloidosis (26,27) is characterized by the deposition of WT TTR in the heart and peripheral nerves, whereas the deposition of one of Ͼ100 different TTR variants is associated with a group of diseases collectively known as the familial amyloidoses. The V30M mutation is the most common familial amyloid polyneuropathy variant and has been found in patients in Japan, Portugal, and Sweden (28,29).…”

mentioning

confidence: 99%

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Green

Foss

Kelly

2005

Proc. Natl. Acad. Sci. U.S.A.

110

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The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K d1 ‫؍‬ 40 nM, Kd2 ‫؍‬ 1.4 M). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements.amyloidogenesis inhibitor ͉ kinetic stabilization F or many years nutritionists and dieticians have noted the health benefits of a soy-based diet, citing the much lower incidence of cancer, including breast cancer, in Asian countries (1-4). The isoflavone genistein (compound 1 in Fig. 1), found in various soy foods at concentrations of 1.9-229 g͞g, is the component of soy implicated in cancer chemoprevention (5). An additional 71-968 g͞g of genistein is present as its O-glucoside conjugate, genistin (2), which is rapidly deglycosylated by intestinal bacteria in vivo. Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6, 7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11-13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.Transthyretin (TTR) is a tetrameric protein composed of identical 127-aa ␤-sheet sandwich subunits (14, 15). TTR functions to transport holo-retinol-binding protein and thyroxine (T4) in the blood and cerebrospinal fluid (16,17). Under denaturing con...

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A review of the amyloidoses that infiltrate the heart

Cited by 62 publications

References 39 publications

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Multiple plasma proteins control atrial natriuretic peptide (ANP) aggregation

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

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