Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis

Jagatheesan, Ganapathy; Rajan, Sudarsan; Petrashevskaya, Natalia; Schwartz, Arnold; Boivin, Greg P.; Arteaga, Grace M.; Solaro, R. John; Liggett, Stephen B.; Wieczorek, David F.

doi:10.1152/ajpheart.01341.2006

Cited by 49 publications

(49 citation statements)

References 32 publications

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“…Although the etiology of the cardiomyopathies remains unclear, experimental evidence shows promise that improving cardiac muscle Ca 2ϩ sensitivity through either pharmacological or genetic approaches can relieve disease-related symptoms (27,28,30,49). Ca 2ϩ sensitizers have attracted growing clinical interest for their potential therapeutic value in treating heart failure and cardiomyopathies that desensitize cardiac muscle to Ca 2ϩ (31).…”

Section: Discussionmentioning

confidence: 99%

“…Strikingly, for any particular class of inherited cardiomyopathies, the apparent Ca 2ϩ sensitivity of TnC and force development are typically altered in a qualitatively similar manner (20,22,25). Furthermore, pharmacological and genetic interventions that rectify the apparent Ca 2ϩ sensitivity of cardiac muscle in transgenic animal models harboring cardiomyopathic genes show promise of alleviating the disease symptoms (27)(28)(29). For instance, modulating TnI, TnT, or tropomyosin (each of which can indirectly tune the Ca 2ϩ sensitivity of TnC) counteracted the abnormal cardiac muscle Ca 2ϩ sensitivities and ameliorated the disease symptoms (28 -30).…”

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confidence: 99%

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Engineered Troponin C Constructs Correct Disease-related Cardiac Myofilament Calcium Sensitivity

Liu

Lee

Biesiadecki

et al. 2012

Journal of Biological Chemistry

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Background: Improved myofilament Ca 2ϩ sensitivity alleviates defects in thin filament bearing disease-causing mutations. Results: By engineering the cardiac muscle Ca 2ϩ sensor troponin C, aberrant myofilament Ca 2ϩ sensitivity can be corrected in vitro. Conclusion: Engineered TnC provides a novel and versatile avenue to reset disease-related myofilament Ca 2ϩ sensitivity. Significance: Engineered TnC could be a new therapeutic strategy for cardiac muscle diseases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Engineered Troponin C Constructs Correct Disease-related Cardiac Myofilament Calcium Sensitivity

Liu

Lee

Biesiadecki

et al. 2012

Journal of Biological Chemistry

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“…And smooth muscle contraction is regulated by interaction with caldesmon. in nonmuscle cells, tPM1 is involved in stabilizing the cytoskeleton actin filaments (1,10,14,21).…”

Section: Introductionmentioning

confidence: 99%

Molecular Cloning and Characteristics of thePSPH, snrpa1andTPM1Genes in Black-Boned Sheep (Ovis Aries)

Leng

et al. 2013

Biotechnology & Biotechnological Equipment

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“…Several studies demonstrate that the FHC phenotype can be modulated through alterations in calcium handling by the myofilaments and calcium buffering (2,4,8,15,22,24). Recently, we examined whether modification of SERCA2a activity and Ca 2ϩ handling would rescue the hypertrophic phenotype in the Tm180 mice (4,7,8,13).…”

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confidence: 99%

“…Recently, we examined whether modification of SERCA2a activity and Ca 2ϩ handling would rescue the hypertrophic phenotype in the Tm180 mice (4,7,8,13). To test the hypothesis that increasing the rate of calcium resequestration into the SR through PLN ablation would attenuate the FHC pathological and physiological phenotype, we crossed the FHC Tm180 mice with PLN KO mice (7).…”

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confidence: 99%

Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

Rajan

Peña

Jegga

et al. 2013

Physiological Genomics

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Rajan S, Pena JR, Jegga AG, Aronow BJ, Wolska BM, Wieczorek DF. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics 45: 764 -773, 2013. First published June 25, 2013 doi:10.1152/physiolgenomics.00023.2013.-Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHCassociated mutation in ␣-tropomyosin: Glu ¡ Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype. tropomyosin; phospholamban; cardiomyopathy; mouse model CARDIOVASCULAR DISEASE IS the leading cause of mortality in the Western world, with heart failure representing one of the fastest growing subgroups over the past decade. Systolic and diastolic dysfunction is common in patients suffering from many types of heart disease and cardiac failure. In addition, hypertrophic growth of cardiomyocytes occurs in many forms of heart failure and may contribute to the pathogenesis of the failure state.Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in contractile proteins of the cardiac sarcomere, Z-disc proteins, and Ca 2ϩ -handling proteins (5). ␣-tropomyosin (Tm), a thin filament protein of the sarcomere, has been found to encode 11 mutations that lead to FHC (23). Previous work in our laboratories established a transgenic mouse model expressing mutant FHC Tm180 protein (1,7,16,17). This mouse develops severe concentric cardiac hypertrophy with si...

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Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis

Cited by 49 publications

References 32 publications

Engineered Troponin C Constructs Correct Disease-related Cardiac Myofilament Calcium Sensitivity

Engineered Troponin C Constructs Correct Disease-related Cardiac Myofilament Calcium Sensitivity

Molecular Cloning and Characteristics of thePSPH, snrpa1andTPM1Genes in Black-Boned Sheep (Ovis Aries)

Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

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