Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice.

Colbert, Melissa C.; Hall, D. Greg; Kimball, Thomas R.; Witt, Sandra A.; Lorenz, John N.; Kirby, Margaret L.; Hewett, Timothy E.; Klevitsky, Raisa; Robbins, Jeffrey

doi:10.1172/jci119727

Cited by 93 publications

(61 citation statements)

References 42 publications

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“…In TG animals, phosphorylated RLC2v could not be detected. These data, in conjunction with the SDS-PAGE analyses, indicate that not only is phosphorylation completely ablated in the TG RLC2v(PϪ), but little endogenous RLC2v remains in the adult ventricles of line 21 (and line 35) 2 TG animals. Ultrastructure of Line 21 RLC2v(PϪ) Hearts-In light of the histological abnormalities observed in lines 21 (Fig.…”

Section: Fig 2 Cardiac Structural Analysesmentioning

confidence: 60%

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Abnormal Cardiac Structure and Function in Mice Expressing Nonphosphorylatable Cardiac Regulatory Myosin Light Chain 2

Sanbe¹,

Fewell²,

Gulick³

et al. 1999

Journal of Biological Chemistry

114

102

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A role for myosin phosphorylation in modulating normal cardiac function has long been suspected, and we hypothesized that changing the phosphorylation status of a cardiac myosin light chain might alter cardiac function in the whole animal. To test this directly, transgenic mice were created in which three potentially phosphorylatable serines in the ventricular isoform of the regulatory myosin light chain were mutated to alanines. Lines were obtained in which replacement of the endogenous species in the ventricle with the nonphosphorylatable, transgenically encoded protein was essentially complete. The mice show a spectrum of cardiovascular changes. As previously observed in skeletal muscle, Ca 2؉ sensitivity of force development was dependent upon the phosphorylation status of the regulatory light chain. Structural abnormalities were detected by both gross histology and transmission electron microscopic analyses. Mature animals showed both atrial hypertrophy and dilatation. Echocardiographic analysis revealed that as a result of chamber enlargement, severe tricuspid valve insufficiency resulted in a detectable regurgitation jet. We conclude that regulated phosphorylation of the regulatory myosin light chains appears to play an important role in maintaining normal cardiac function over the lifetime of the animal.The roles of the regulatory myosin light chains (RLCs) 1 and the reversible post-translational modifications they undergo in striated muscle are beginning to be defined. In skeletal muscle, a serine at the amino end of the protein can be phosphorylated by a sarcoplasmic kinase (1), and it is now clear that RLCs in the different striated muscles are phosphorylated to differing degrees, leading presumably to different physiological effects. In smooth muscle, RLC phosphorylation by myosin light chain kinase (MLCK), which is activated by a Ca 2ϩ /calmodulin-dependent pathway, is responsible for initiating muscle contraction (2, 3). However, in skeletal and cardiac muscle, in which the thin, rather than thick, filament mediates control of contraction, RLC phosphorylation does not activate contraction but appears to play a modulatory role. In skinned skeletal muscle fibers, RLC phosphorylation increases sensitivity to activating Ca 2ϩ such that there is a significant leftward shift in the force-Ca 2ϩ relationship (4 -6). Increased RLC phosphorylation in skeletal muscle is also associated with potentiation of isometric twitch tension with repeated activation and inactivation of contraction (7, 8), rate of force production (9 -11), and maximum Ca 2ϩ -stimulated MgATPase activity (12). The mechanistic basis for the effects of RLC phosphorylation in striated muscle is hypothesized to be a lessening of the weak interaction of the myosin head with the myosin backbone and is probably due to a net charge change in a critical region of the protein (13). Upon phosphorylation, the myosin heads move away from the backbone to a position closer to actin, which presumably increases the rate at which myosin-actin interaction...

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Section: Fig 2 Cardiac Structural Analysesmentioning

confidence: 60%

“…Cardiac Remodeling in Older Mice-To assess the contractile and structural consequences the above changes might have on whole heart function, mice (line 21) aged 16 weeks were subjected to echocardiography (34,35). In RLC2v(PϪ) TG mice, shortening fractions were nearly the same.…”

Section: Molecular Markers Of Hypertrophy Show a Dose Response-mentioning

confidence: 99%

Abnormal Cardiac Structure and Function in Mice Expressing Nonphosphorylatable Cardiac Regulatory Myosin Light Chain 2

Sanbe¹,

Fewell²,

Gulick³

et al. 1999

Journal of Biological Chemistry

114

102

View full text Add to dashboard Cite

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“…RACK 10-wk-old mice or their nontransgenic (wild-type) littermate controls were anesthetized with i.p. avertin, and their hearts were rapidly removed and cannulated via the aorta for retrograde perfusion as described (26). Care was taken to have the hearts perfused within 90 sec of removal.…”

Section: Methodsmentioning

confidence: 99%

Sustained in vivo cardiac protection by a rationally designed peptide that causes ɛ protein kinase C translocation

Dorn

Souroujon

Liron

et al. 1999

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

339

298

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Brief periods of cardiac ischemia trigger protection from subsequent prolonged ischemia (preconditioning). Protein kinase C (PKC) has been suggested to mediate preconditioning. Here, we describe an PKC-selective agonist octapeptide, receptor for activated C-kinase (RACK), derived from an PKC sequence homologous to its anchoring protein, RACK. Introduction of RACK into isolated cardiomyocytes, or its postnatal expression as a transgene in mouse hearts, increased PKC translocation and caused cardio-protection from ischemia without any deleterious effects. Our data demonstrate that PKC activation is required for protection from ischemic insult and suggest that small molecules that mimic this PKC agonist octapeptide provide a powerful therapeutic approach to protect hearts at risk for ischemia.preconditioning ͉ hypoxia ͉ transgenic pseudoreceptors for activated C-kinase ͉ ischemia

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“…␤-MyHCcre transgenic mice were generated that express the Cre recombinase in slow skeletal and embryonic cardiac muscle. The Cre coding sequence was linked to the 5.6-kb mouse ␤-myosin heavy chain promoter (38) and SV40 small t-intron and polyadenylation sequences. The transgene was released using SfiI and NotI and used for pronuclear microinjection.…”

mentioning

confidence: 99%

Genetic Loss of Calcineurin Blocks Mechanical Overload-induced Skeletal Muscle Fiber Type Switching but Not Hypertrophy

Parsons

Millay

Wilkins

et al. 2004

Journal of Biological Chemistry

164

162

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The serine/threonine phosphatase calcineurin is an important regulator of calcium-activated intracellular responses in eukaryotic cells. In higher eukaryotes, calcium/ calmodulin-mediated activation of calcineurin facilitates direct dephosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T-cells (NFAT). Recently, controversy has surrounded the role of calcineurin in mediating skeletal muscle cell hypertrophy. Here we examined the ability of calcineurin-deficient mice to undergo skeletal muscle hypertrophic growth following mechanical overload (MOV) stimulation or insulin-like growth factor-1 (IGF-1) stimulation. Two distinct models of calcineurin deficiency were employed: calcineurin A␤ gene-targeted mice, which show a Ϸ50% reduction in total calcineurin, and calcineurin B1-LoxP-targeted mice crossed with a myosin light chain 1f cre knock-in allele, which show a greater than 80% loss of total calcineurin only in skeletal muscle. Calcineurin A␤؊/؊ and calcineurin B1-LoxP(fl/fl)-MLC-cre mice show essentially no defects in muscle growth in response to IGF-1 treatment or MOV stimulation, although calcineurin A␤؊/؊ mice show a basal defect in total fiber number in the plantaris and a mild secondary reduction in growth, consistent with a developmental defect in myogenesis. Both groups of genetargeted mice show normal increases in Akt activation following MOV or IGF-1 stimulation. However, overloadmediated fiber-type switching was dramatically impaired in calcineurin B1-LoxP(fl/fl)-MLC-cre mice. NFAT-luciferase reporter transgenic mice failed to show a correlation between IGF-1-or MOV-induced hypertrophy and calcineurin-NFAT-dependent signaling in vivo. We conclude that calcineurin expression is important during myogenesis and fiber-type switching, but not for muscle growth in response to hypertrophic stimuli.

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Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice.

Cited by 93 publications

References 42 publications

Abnormal Cardiac Structure and Function in Mice Expressing Nonphosphorylatable Cardiac Regulatory Myosin Light Chain 2

Abnormal Cardiac Structure and Function in Mice Expressing Nonphosphorylatable Cardiac Regulatory Myosin Light Chain 2

Sustained in vivo cardiac protection by a rationally designed peptide that causes ɛ protein kinase C translocation

Genetic Loss of Calcineurin Blocks Mechanical Overload-induced Skeletal Muscle Fiber Type Switching but Not Hypertrophy

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