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. 1997 Apr 29;94(9):4710-5.
doi: 10.1073/pnas.94.9.4710.

Ras-dependent pathways induce obstructive hypertrophy in echo-selected transgenic mice

K R Gottshall  1 , J J Hunter, N Tanaka, N Dalton, K D Becker, J Ross Jr, K R Chien
Affiliations

Ras-dependent pathways induce obstructive hypertrophy in echo-selected transgenic mice

K R Gottshall et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
Intraventricular pressure/velocity gradients. (A) Pullback of micromanometer-tip catheter from LV to aorta. A decrease in systolic pressure of 35 mmHg is evident within the LV cavity. LVP, LV pressure. AoP, aortic pressure. (B) Doppler ultrasound signal from same animal with sample volume placed in the mid-ventricular region (by color-encoded Doppler signal). Signal below baseline (velocity away from transducer) occurs during systole; that above baseline (velocity toward transducer) occurs during early diastole.
Figure 2
Figure 2
Quantitative myocyte disarray. Results are shown as area fraction (mean + SEM) of longitudinally oriented myocytes in intraventricular septum that is disarrayed. ∗, P < 0.001 vs. both other groups.
Figure 3
Figure 3
Northern blot analysis. (A) Representative Northern blot showing probes for ANP, MLC2v (n = 4), and GAPDH (each lane represents RNA from one animal). (B) Fold induction (over WT) of mRNAs for cardiac α-actin (n = 7, 11, 8), smooth muscle α-actin (n = 7, 12, 8), and MLC2v (n = 7, 11, 8) (corrected for differences in loading using GAPDH signal). (C) Fold induction of mRNAs for skeletal α-actin (n = 16, 17, 12; includes an additional group of animals not analyzed by echocardiography), MLC2a (n = 7, 7, 7), and β-MHC (n = 7, 8, 8). (D) Fold induction of ANP (n = 11, 8, 7) and BNP (n = 7, 7, 7). Note that n = WT, TAC, and RAS values respectively. Data are mean + SEM; ∗, P < 0.05 vs. WT.
Figure 4
Figure 4
Survival analysis. RAS, matings between homozygotes of echocardiographically selected substrain of MLC–Ras; Het, matings between unselected MLC–Ras heterozygotes. The survival curves are significantly different (P < 0.001).
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