Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart.

Abstract

The ␣ -myosin heavy chain ( ␣ -MyHC) is the major contractile protein expressed in the myocardium of adult mice. We have produced mice carrying a null mutation of ␣ -MyHC by homologous recombination in murine ES cells. Homozygous null animals die between 11 and 12 d in utero of gross heart defects, while ␣ -MyHC ϩ / Ϫ heterozygotes survive and appear externally normal. The presence of a single functional ␣ -MyHC ϩ allele in heterozygous animals results in reduced levels of the transcript and protein as well as fibrosis and alterations in sarcomeric structure. Examination of heart function using a working heart preparation revealed severe impairment of both contractility and relaxation in a subset of the ␣ -MyHC ϩ / Ϫ animals. Thus, two ␣ -MyHC ϩ alleles are necessary for normal cardiac development, and hemizygosity for the normal allele can result in altered cardiac function. ( J. Clin. Invest. 1996Invest. . 98:1906Invest. -1917

Modeling the Transition From Decompensated to Pathological Hypertrophy

“…Moreover, whereas pathologically stressed hearts may initially compensate, markers of physiological hypertrophy should not be in evidence. However, we observed a significant increase in myosin heavy chain‐β expression that did not alter the myosin heavy chain‐β/α ratio, an adaptive response thought to preserve function by increasing myocardial efficiency 38. Physiological and pathophysiological hypertrophies are generally described as separate conditions rather than as different phases.…”

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

“…On the other hand, hearts in the Kidney KOs appeared virtually normal, indicating that vascular injury and fibrosis in the heart were also consequences of elevated blood pressure rather than local actions of cardiac AT 1 receptors. Cardiac hypertrophy is associated with characteristic alterations in gene expression, including up-regulation of ANP and BNP (31,32), and recapitulation of fetal patterns for expression of myosin heavy chains (33,34). It has been suggested that activation of AT 1 receptors in cardiomyocytes may be sufficient to trigger this transcription profile (34,35).…”

“…Although our evaluations of heart weight and histology indicate a dominant effect of blood pressure on cardiac pathology, we considered the possibility that these assessments might not be sufficiently sensitive to detect cellular actions of AT 1 receptors in cardiac myocytes. During hypertrophic cardiac remodeling, gene expression in myocardium undergoes characteristic alterations, including enhanced expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), along with recapitulation of fetal gene expression patterns for myosin heavy chains (MHC) characterized by a down-regulation of ␣-MHC and up-regulation of the ␤-MHC isoform (31)(32)(33)(34). Previous studies have suggested that Ang II may stimulate these processes (35,36).…”

Cell biology of embryonic migration

“…Mouse knockouts of cell migration components or other proteins with direct effects on cell migration Protein Function Type Phenotype Reference α skeletal muscle actin Actin Cytoskeleton Total Postnatal death at P1-9, marked loss of body weight; upregulation of other actin isoforms (Crawford et al, 2002) α smooth muscle actin Actin Cytoskeleton Total Viable; impaired vascular contractility and blood pressure homeostasis; upregulation of other actin isoforms (Schildmeyer et al, 2000) α cardiac actin Actin Cytoskeleton Total Perinathal lethality; cardiac hypertrophy and heart muscle abnormalities; upregulation of other actin isoforms (Kumar et al, 1997) β non-muscle actin Actin Cytoskeleton Total Death after E9.5 (Shawlot et al, 1998) γ non-muscle actin Actin Cytoskeleton Skeletal muscle-specific Muscle weakness, necrosis and degeneration (Sonnemann et al, 2006) Tropomyosin Actin Cytoskeleton Total Death before morula stage (Hook et al, 2004) Mena Actin Cytoskeleton Total Viable, with misrouted axons and defects in the nervous system (Lanier et al, 1999) Mena, VASP, Evl triple null Actin Cytoskeleton Total Defects in brain development, neuritogenesis, and neural tube closure Filamin-B Actin Cytoskeleton Total Skeletal malformations and impaired microvascular development (Zhou et al, 2007) Gelsolin (or ADF) Actin Cytoskeleton Total Defects in fibroblast and platelet motility and lamellar responses (Witke et al, 1995) Nonmuscle myosin II-B Actin Cytoskeleton Total Embryonic and perinatal lethality with severe heart defects (Tullio et al, 1997) Myosin heavy chain II-A Actin Cytoskeleton Total Failure in embryonic patterning, embryonic lethality by E7.5 (Conti et al, 2004) Cardiac alpha myosin, heavy chain Actin Cytoskeleton Total Embryonic lethality between E11 and 12 with gross heart defects (Jones, 1996) (Imamoto and Soriano, 1993;Nada et al, 1993) Ephrin B1 Transmembrane signaling Total Neural crest cell misguidance (cranial and cardiac, but not trunk) (Davy et al, 2004) Angiomotin Transmembrane signaling Total Death between E11-E11.5, severe vascular insufficiency in intersomitic regions, dilated vessels in the brain (Aase et al, 2007) Birth Defects Res C Embryo Today. Author manuscript; available in PMC 2009 June 1.…”