title: Ras-dependent pathways induce obstructive hypertrophy in echo-selected transgenic mice.
abstract: To overcome the genetic and interindividual variability frequently noted in complex phenotypes, we used echocardiographic selection to develop a substrain of myosin light chain (MLC)-Ras (RAS) transgenic mice with an enhanced ventricular hypertrophic phenotype. These echo-selected mice were then compared with wild-type (WT) animals and a pressure overload hypertrophy model (transverse aortic constriction; TAC). Echocardiography demonstrated increased wall thickness in RAS compared with the other groups. We developed novel miniaturized physiological technology to quantitatively identify in vivo intraventricular gradients; increased systolic Doppler velocity was seen in the left ventricle (LV) in 69% of RAS vs. none of WT or TAC. Intracavitary pressure gradients were present in 3 of 10 RAS vs. none of TAC or WT. Passive diastolic LV stiffness was not different among the three groups. Myofibrillar disarray was present in all RAS animals and was significantly more extensive (21.7% area fraction) than in TAC (1.5%) or WT (0.0%). RAS mice had selective induction of natriuretic peptide genes in the LV, a pattern distinct from that induced by pressure overload. Juvenile mortality was significantly increased in the offspring of echo-selected RAS parents. We conclude that adaptation of echocardiography to the mouse permits selection for cardiac phenotypes, and that selectively inbred MLC-Ras transgenic mice faithfully reproduce the molecular, physiological, and pathological features of human hypertrophic cardiomyopathy (HCM). Because previous studies support the concept that hypertrophy in human HCM is secondary to dysfunction created by sarcomeric protein mutations, the current studies suggest that Ras-dependent pathways might play a similar role in forms of human HCM.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0613, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Gottshall
authors.forename: J J
authors.initials: JJ
authors.lastname: Hunter
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Dalton
authors.forename: K D
authors.initials: KD
authors.lastname: Becker
authors.forename: J
authors.initials: J
authors.lastname: Ross
authors.forename: K R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000367:Age Factors; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression; D014644:Genetic Variation; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012641:Selection, Genetic; D015398:Signal Transduction; D014463:Ultrasonography; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018994:Myosin Light Chains; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D018631:ras Proteins