Disease relevance of Myh6

• Susceptibility to Coxsackievirus B3-induced chronic myocarditis maps near the murine Tcr alpha and Myhc alpha loci on chromosome 14 [1].
• A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression of a cardiac alpha-myosin transgene including the R(403)Q mutation and a deletion of a segment of the actin-binding domain [2].
• A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of familial hypertrophic cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise [3].
• Previously, we described transgenic mice with alpha-myosin heavy chain-directed expression of a constitutively active mutant alpha1B-AR that had a phenotype of myocardial hypertrophy (Milano, C. A., Dolber, P. C., Rockman, H. A., Bond, R. A., Venable M. E., Allen, L. F., and Lefkowitz, R. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10109-10113) [4].
• In the present study, we examined the role of gp130 in pressure overload-induced cardiac hypertrophy using transgenic (TG) mice, which express a dominant negative mutant of gp130 in the heart under the control of alpha myosin heavy chain promoter [5].

High impact information on Myh6

• The myhc alpha (334-352) peptide strongly induced myocarditis when administered to A/J mice, which was histologically indistinguishable from that induced by myosin [6].
• The myhc alpha (334-352) epitope was present in cardiac myosin and not skeletal muscle myosins, providing a biochemical basis for the cardiac specificity of this autoimmune disease [6].
• One peptide, myhc alpha (325-357) strongly stimulated the Seu.5 T cells, localizing the epitope to this region of the myhc alpha molecule [6].
• Importantly, the myhc alpha (334-352) epitope was able to bind to I-Ak molecules on the surface of antigen-presenting cells in a stable manner [6].
• Late deletion of Gata4 by Cre recombinase driven by the alpha myosin heavy chain promoter did not selectively affect RV development or generation of endocardial cushion mesenchyme but did result in marked myocardial thinning with decreased cardiomyocyte proliferation, as well as double-outlet RV [7].

Biological context of Myh6

• We conclude that 45-MHz echocardiography is an excellent tool for assessing cardiac physiology in neonatal mice and that the concentration of Gln403 alpha cardiac MHC in myocytes influences both cell function and cell viability [8].
• A mouse model of FHC resulting from a mutation in the alpha-myosin heavy-chain (Arg403Gln) was used to study the electrophysiologic phenotype of this disease [9].
• We used a transgenic ES cell lineage expressing enhanced green fluorescent protein (EGFP) under the control of the alpha-myosin heavy chain (alpha-MHC) promoter (palphaMHC-EGFP) to investigate the effects of 33 small molecules interfering with several signalling cascades on cardiomyogenesis [10].
• We developed novel, fluorescent-based, myocardial, cellular transplantation systems in order to study these questions in murine embryos and report the irreversible nature of chamber specification with respect to the downregulation of atrial myosin light chain 2 (MLC-2a) and alpha myosin heavy chain (alpha-MHC) [11].
• In this study, we have rescued these high expression beta-tropomyosin mice by turning off the alpha-myosin heavy chain promoter, which is driving the beta-tropomyosin transgene [12].

Anatomical context of Myh6

• The alpha-myosin heavy chain (alpha-MyHC) is the major contractile protein expressed in the myocardium of adult mice [13].
• We used small-amplitude (0.25%) length-perturbation analysis to examine the mechanical properties of skinned left ventricular papillary muscle strips from mouse hearts bearing the R403Q mutation in the alpha-myosin heavy chain (alphaMHC403/+) [14].
• This down-regulation of the alpha-myosin heavy chain promoter was accomplished by the administration of 5-propyl-2-thiouracil, which disrupts thyroid hormone synthesis and inhibits promoter activity through thyroid regulatory elements located in the 5'-flanking region of the promoter [12].
• To determine whether recruitment into the myocardial lineage also takes place in these regions, the spatiotemporal pattern of expression of alpha-Sma and of the myocardial markers sarcoplasmatic reticulum calcium ATPase (Serca2a), alpha-myosin heavy chain (Mhc), and beta-Mhc were examined [15].
• In vitro, Cre driven by cardiac-specific alpha-myosin heavy chain (alphaMyHC) sequences elicited recombination selectively at loxP sites in purified cardiac myocytes, but not cardiac fibroblasts [16].

Associations of Myh6 with chemical compounds

• To assess the importance of the intergenic region in directing expression of the alpha-cardiac MHC gene, a fragment containing the 3'-end of the beta-cardiac gene and the 5'-end of the alpha-cardiac gene was linked to a chloramphenicol acetyltransferase gene and used to generate transgenic mice [17].
• In this study, we used the alpha-myosin heavy chain (alphaMHC) promoter to generate transgenic mice overexpressing angiotensin II type 1 (AT1a) receptor selectively in cardiac myocytes [18].
• The cardiac-restricted alpha-myosin heavy chain promoter was used to target expression of a mutant TGF-beta(1) cDNA harboring a cysteine-to-serine substitution at amino acid residue 33 [19].
• This study provides direct evidence that USF, a member of the basic helix-loop-helix leucine zipper family, binds to MLE1, HF-1a, and PRE B sites and suggests that it is a component of protein complexes that may coordinately control the expression of MLC-2v and alpha-myosin heavy-chain genes [20].
• In the absence of DMSO, dynorphin B triggered GATA-4 and Nkx-2.5 gene expression and led to the appearance of both alpha-myosin heavy chain and myosin light chain-2V transcripts, two markers of cardiac differentiation [21].

Physical interactions of Myh6

• Transgenic mice were generated by using the alpha-myosin heavy chain promoter coupled to the coding sequence of a constitutively active mutant alpha 1B-adrenergic receptor (AR) [22].
• Here we generated transgenic mice expressing a tamoxifen-inducible Cre recombinase protein fused to two mutant estrogen-receptor ligand-binding domains (MerCreMer) under the control of the alpha-myosin heavy chain promoter [23].

Regulatory relationships of Myh6

• Rescue of high expression beta-tropomyosin transgenic mice by 5-propyl-2-thiouracil. Regulating the alpha-myosin heavy chain promoter [12].
• To better understand the role of triadin 1 in SR-Ca(2+) release, we studied the time-dependent expression of SR proteins and contractility in atria of 3-, 6-, and 18-wk-old transgenic mice overexpressing canine cardiac triadin 1 under control of the alpha-myosin heavy chain (MHC) promoter [24].
• To determine the influence of Bcl-2 on the developmental biology of myocytes, we analyzed the population dynamics of this cell type in the heart of transgenic (TG) mice overexpressing Bcl-2 under the control of the alpha-myosin heavy chain promoter [25].
• To increase IK1 density, a pore-forming subunit of the Kir2.1 (green fluorescent protein-tagged) channel was expressed in the heart under control of the alpha-myosin heavy chain promoter [26].
• When mouse alpha-tropomyosin cDNA under the control of a cardiac-specific alpha-myosin heavy chain promoter was transfected into the mutant hearts, tropomyosin expression was enhanced resulting in the formation of well-organized sarcomeric myofibrils [27].

Other interactions of Myh6

• Analyses of phospholamban transcript levels relative to alpha-myosin heavy chain (alpha-MHC) revealed a 3-fold higher phospholamban abundance in the ventricle compared with the atrium of the FVB/N murine strain [28].
• In all the stages of development, the beating cells in the EBs of both groups expressed beta-actinin, myosin light chain isoform 2V, cardiac alpha-myosin heavy chain (alpha-MHC), and cardiac beta-myosin heavy chain (beta-MHC) [29].
• METHODS AND RESULTS: Postnatal transgenic cardiac-specific overexpression of MLC2v was achieved by use of the alpha-myosin heavy chain promoter [30].
• This is the first report demonstrating that transcriptional regulatory elements located within the alpha-myosin heavy chain promoter can be manipulated to rescue potentially lethal phenotypes, such as high expression beta-tropomyosin transgenic mice [12].
• We examined the effect of adhesion signaling including Src and focal adhesion kinase (FAK) on cardiogenesis in mouse ES cells using alpha-myosin heavy chain promoter-driven enhanced green fluorescent protein or luciferase as reporters [31].

Analytical, diagnostic and therapeutic context of Myh6

• Primer extension and polymerase chain reaction (PCR) analyses were used to define the transcriptional start site and the 5'-organization of the alpha-cardiac MHC gene [17].
• All cardiomyocytes appeared to be positive in immunofluorescence assays with monoclonal antibodies against cardiac-specific alpha-cardiac MHC, as well as muscle-specific sarcomeric myosin heavy chain and desmin [32].
• Our results indicate that the jmj floxed allele converts to a null allele in a heart-specific manner when embryos homozygous for the floxed jmj allele and carrying the alpha-myosin heavy chain promoter-Cre transgene were analyzed by Southern and Northern blot analyses [33].
• Both enzyme-linked immunospot (ELISPOT) and cytokine flow cytometry (CFC) assays were suitable for the detection and characterization of myhca-specific Th cells during acute myocardial inflammation and the late healing phase of the disease [34].
• The proportion of myocardium positively immunostained by antibodies against alpha-myosin heavy chain and cardiac troponin I was greater in the infarcted area with embryonic stem cell transplantation than in the injured myocardium with medium injection [35].

References