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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1077.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Increased Atherosclerosis and Smooth Muscle Cell Hypertrophy in Natriuretic Peptide Receptor A^-/-Apolipoprotein E^-/- Mice

Matthew R. Alexander^*; Joshua W. Knowles^*; Toshio Nishikimi; Nobuyo Maeda

From the Department of Pathology and Laboratory Medicine (M.R.A., N.M.) and the Curriculum in Genetics and Molecular Biology (J.W.K., N.M.), University of North Carolina, Chapel Hill, and the Department of Hypertension and Cardiorenal Medicine (T.N.), Dokkyo University School of Medicine, Mibu, Japan.

Correspondence to Nobuyo Maeda, PhD, Department of Pathology and Laboratory Medicine, University of North Carolina, 710 Brinkhous-Bullitt Bldg, Chapel Hill, NC 27599-7525. E-mail nobuyo{at}med.unc.edu

Objective— Natriuretic peptide signaling is important in the regulation of blood pressure as well as in the growth of multiple cell types. To examine the role of natriuretic peptide signaling in atherosclerosis, we crossbred mice that lack natriuretic peptide receptor A (NPRA; Npr1^-/-) with atherosclerosis-prone mice that lack apolipoprotein E (apoE; Apoe^-/-).

Methods and Results— Doubly deficient Npr1^-/-Apoe^-/- mice have increased blood pressure relative to Npr1^+/+Apoe^-/- mice (118±4 mm Hg compared with 108±2 mm Hg, P<0.05) that is coincident with a 64% greater atherosclerotic lesion size (P<0.005) and more advanced plaque morphology. Additionally, aortic medial thickness is increased by 52% in Npr1^-/-Apoe^-/- mice relative to Npr1^+/+Apoe^-/- mice (P<0.0001). Npr1^-/-Apoe^-/- mice also have significantly greater cardiac mass (9.0±0.3 mg/g body weight) than either Npr1^+/+Apoe^-/- mice (5.8±0.2 mg/g) or Npr1^-/-Apoe^+/+ mice (7.1±0.2 mg/g), suggesting that the lack of both NPRA and apoE synergistically enhances cardiac hypertrophy.

Conclusions— These data provide evidence that NPR1 is an atherosclerosis susceptibility locus and represents a potential link between atherosclerosis and cardiac hypertrophy. Our results also suggest roles for Npr1 as well as Apoe in regulation of hypertrophic cell growth.

Key Words: natriuretic peptide receptor A • atherosclerosis • cardiac hypertrophy • vascular smooth muscle cells

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