Disease relevance of Myl3

• To determine if activation of ras-dependent intracellular signaling pathways is sufficient to induce in vivo hypertrophy, transgenic mice were created that express oncogenic ras in the cardiac ventricular chamber [1].
• However, despite the substitution of myosin light chain 2a, ultrastructural analysis revealed defects in sarcomeric assembly and an embryonic form of dilated cardiomyopathy characterized by a significantly reduced left ventricular ejection fraction in mutant embryos compared with wild type littermates [2].
• Ventricular tachyarrhythmia could not be induced in either type of mouse [3].
• Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice [4].
• Other changes include atrial enlargement and fibrosis, and diffuse myocytolysis, Physiological analyses using ventricular muscle strip preparations from these mice reveal that both myocardial contraction and relaxation parameters are severely impaired [5].

Psychiatry related information on Myl3

• These results support the hypothesis that cTnT isoform amino-terminal differences affect myofilament function and suggest that hcTnT(1) expression levels present during human development and in human heart disease can affect in vivo ventricular function [6].
• They had no or moderate macrocephaly; moderate ventricular dilatation and preserved general motor activity; they all presented spontaneous ventriculostomies communicating the ventricles with the subarachnoid space, indicating that such communications play a key role in the long survival of these mice [7].
• In a patient whose Creutzfeldt-Jakob disease with congophilic kuru plaques that was proved at necropsy, the early brain CT showed low-density areas in the cerebral white matter before cortical atrophy and ventricular enlargement became apparent [8].
• However, prior alcohol consumption doubled recovery of left ventricular developed pressure (68 +/- 8 vs. 33 +/- 8 mmHg for controls; n = 10, P < 0.05) and reduced creatine kinase release by half (0.26 +/- 0.04 vs. 0.51 +/- 0.08 U x min(-1) x g wet wt(-1) for controls; n = 10, P < 0.05) [9].

High impact information on Myl3

• The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient [10].
• To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations [11].
• Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium [11].
• Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease [11].
• FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death [12].

Chemical compound and disease context of Myl3

• Left ventricular hypertrophy was observed on echocardiography (1.25+/-0.05 mm vs. 0.86+/-0.02 mm in cTnI-wt, P<0.01), associated with a significant 4-fold increase in RNA markers of hypertrophy, ANF and BNP [13].
• AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human [14].
• The sinus cycle length and refractory periods prolonged on procainamide or quinidine, but no tachyarrhythmias could be induced with atrial or ventricular programmed stimulation [15].
• However, calcineurin activity was severely depressed in left ventricular tissue of untreated aortic stenosis mice compared with control mice and was further reduced by cyclosporine treatment [16].
• The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model [17].

Biological context of Myl3

• Transcripts for the ventricular/slow (MLC1V) and another fast skeletal myosin light chain (MLC3F) are not detected in skeletal muscle before 15 d p.c., which marks the beginning of the fetal stage of muscle development [18].
• Taken together, this provides evidence for early positional specification of MLC-2v gene expression in the primitive heart tube and indicates regional specification of part of the ventricular muscle gene program can precede ventricular septation during mammalian cardiogenesis [19].
• To study the process of ventricular specification during cardiogenesis, we examined the in situ expression of cardiac ventricular myosin light chain 2 (MLC-2v) mRNA during murine embryogenesis [19].
• Morphological analysis of these rescued mice show a moderate pathological phenotype, characterized by atrial myocytolysis; echocardiographic analyses demonstrate altered ventricular functions, such as peak filling rates and left ventricular fractional shortening [20].
• An increase in left atrial mass, in the absence of transgene expression in that chamber, further supported physiologically abnormal left ventricular diastolic function [1].

Anatomical context of Myl3

• Like MHC beta, MLC1V transcripts become restricted to ventricular myocytes, but at a slower rate [21].
• Between 7.5 and 8 d post coitum (p.c.), the newly formed cardiac tube begins to express MHC alpha, MHC beta, MLC1 atrial (MLC1A), and MLC1 ventricular (MLC1V) gene transcripts at high levels throughout the myocardium [21].
• Sinus node recovery times after carbachol and sinus cycle lengths were shorter and ventricular effective refractory periods were greater in KO mice than in WT mice [3].
• Decreased fetal cardiac outflow mean velocity, increased proportion of isovolumetric contraction time of the cardiac cycle, and increased pulsatility indices of the descending aorta and inferior vena cava were related to elevated ventricular BNP mRNA levels [22].
• cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform [6].

Associations of Myl3 with chemical compounds

• Recovery kinetics of intracellular Ca(2+) transients recorded from isolated ventricular myocytes at 37 degrees C (tau = 93 +/- 4 ms, n = 18) resembled the APD(90) ERC kinetics [23].
• The fetal ventricular BNP mRNA levels were about 2.6-fold in the LPS group compared with the control group [22].
• Our results do not provide evidence to support an extra-cardiac origin of the ventricular CS [24].
• This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; these parameters at baseline in the transgenic animals were equal to those observed in control animals maximally stimulated with isoproterenol [25].
• Akt-transgenic mice also showed a remarkable increase in cardiac contractility compared with wild-type controls as demonstrated by the analysis of left ventricular (dP/dt(max)) in an invasive hemodynamic study, although with graded dobutamine infusion, the maximum response was not different from that in controls [26].

Physical interactions of Myl3

• METHODS: Cardiac beta-AR density was measured by [125I]-iodocyanopindolol binding to ventricular membranes [27].
• The pattern of VSV immunoreactivity supports the idea that following infection of the olfactory bulb glomeruli, VSV spreads via both ventricular surfaces and retrograde transport within axons of neuromodulatory transmitter systems innervating the olfactory bulb [28].

Regulatory relationships of Myl3

• Nkx2.2 was widely expressed in the ventricular zone of presumptive ZLI and also as a narrow band in the mantle zone [29].
• MLC2v is strongly expressed in the ventricular myocardium and distinctly lower in the outflow tract and atrioventricular canal [30].
• Additionally, wild-type ventricular muscle cells grafted into the wild-type background appropriately downregulate MLC-2a and alpha-MHC [31].
• Irx1 and Irx2 were found to be expressed specifically in the ventricular septum from the onset of its formation onward [32].
• Versican is expressed strongly in the trabeculated ventricular myocardium, whereas the compact proliferative zone has lower transcript abundance [33].

Other interactions of Myl3

• Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction [34].
• As assessed by hybridization with a specific MLC-2v riboprobe, mRNA expression can be found in the ventricular region at day 8.0 postcoitum (pc) [19].
• In neonates, MLC2a continues to be expressed around both right and left semilunar valves, the outlet septum and the non-trabeculated right ventricular outlet [30].
• 3. Results: Stress-induced increases in the PNMT mRNA and protein levels observed in WT mice were almost completely absent in CRH KO mouse adrenal medulla, stellate ganglia, and cardiac atria, while ventricular PNMT mRNA elevation was not CRH-dependent [35].
• We conclude that Irx4 is not sufficient for ventricular chamber formation but is required for the establishment of some components of a ventricle-specific gene expression program [36].

Analytical, diagnostic and therapeutic context of Myl3

• Ventricular region-restricted expression of the luciferase reporter in the embryonic heart, as assessed by immunofluorescence and direct assay of reporter activity in microdissected atrial and ventricular muscle specimens, was confirmed from at least day 15 pc on [19].
• Ventricular ectopy was present only in MyBP-C(t/t) mice during ambulatory ECG recordings [37].
• In situ hybridization studies during mouse embryogenesis revealed cardiac specific expression throughout days 8-16 postcoitum, with atrial restricted expression from day 12 and qualitatively greater atrial expression than ventricular from day 9 [38].
• Measurement of the extent and speed of volume displacement of the isotonically contracting hearts with a specially constructed capacitance transducer revealed that ventricular inotropic responsiveness also appeared after 17-19 days [39].
• In vivo analysis of left ventricular systolic function using M mode and pulsed-wave Doppler echocardiography revealed decreases in fractional shortening (79%) and the normalized mean velocity of circumferential shortening (67%) in transgenic mice compared to wild type (100%) mice [40].

References