title: Smooth muscle LDL receptor-related protein-1 deletion induces aortic insufficiency and promotes vascular cardiomyopathy in mice.
abstract: Valvular disease is common in patients with Marfan syndrome and can lead to cardiomyopathy. However, some patients develop cardiomyopathy in the absence of hemodynamically significant valve dysfunction, suggesting alternative mechanisms of disease progression. Disruption of LDL receptor-related protein-1 (Lrp1) in smooth muscle cells has been shown to cause vascular pathologies similar to Marfan syndrome, with activation of smooth muscle cells, vascular dysfunction and aortic aneurysms. This study used echocardiography and blood pressure monitoring in mouse models to determine whether inactivation of Lrp1 in vascular smooth muscle leads to cardiomyopathy, and if so, whether the mechanism is a consequence of valvular disease. Hemodynamic changes during treatment with captopril were also assessed. Dilation of aortic roots was observed in young Lrp1-knockout mice and progressed as they aged, whereas no significant aortic dilation was detected in wild type littermates. Diastolic blood pressure was lower and pulse pressure higher in Lrp1-knockout mice, which was normalized by treatment with captopril. Aortic dilation was followed by development of aortic insufficiency and subsequent dilated cardiomyopathy due to valvular disease. Thus, smooth muscle cell Lrp1 deficiency results in aortic dilation and insufficiency that causes secondary cardiomyopathy that can be improved by captopril. These findings provide novel insights into mechanisms of cardiomyopathy associated with vascular activation and offer a new model of valvular cardiomyopathy.
authors: Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors: Joshua E
authors: JE
authors: Basford
authors: Sheryl
authors: S
authors: Koch
authors: Ahmad
authors: A
authors: Anjak
authors: Vivek P
authors: VP
authors: Singh
authors: Eric G
authors: EG
authors: Krause
authors: Nathan
authors: N
authors: Robbins
authors: Neal L
authors: NL
authors: Weintraub
authors: David Y
authors: DY
authors: Hui
authors: Jack
authors: J
authors: Rubinstein
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001022:Aortic Valve Insufficiency / Q000000981:diagnostic imaging / Q000235:genetics*; D001794:Blood Pressure; D001808:Blood Vessels / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000503:physiopathology*; D017353:Gene Deletion; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism*; D010766:Phosphorylation; D051899:Smad2 Protein / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051899:Smad2 Protein; C497783:Smad2 protein, mouse