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.
Highlights
Genetic and environmental factors that diminish elasticity and increase vascular stiffness lead to increased risk of atherosclerosis, aortic aneurysm, and vascular dysfunction through several distinct mechanisms [1,2]
Significant dilation was observed in the aortic roots of smLrp1-/- mice compared to smLrp1+/+ mice beginning at 16 weeks of age (1.37 ± 0.05 mm vs.1.7 ± 0.1 mm; P
Hematoxylin and eosin stained cross-sections of the ascending aorta of 40-week old mice demonstrated the extent of dilation and medial thickening observed in smLrp1-/- mice (Figure 2D)
Summary
Genetic and environmental factors that diminish elasticity and increase vascular stiffness lead to increased risk of atherosclerosis, aortic aneurysm, and vascular dysfunction through several distinct mechanisms [1,2]. Fibrillin-1 deficiency activates transforming growth factor-β (TGF-β) signaling pathways, leading to elevated collagen synthesis and matrix metalloproteinase-mediated disruption of the elastic fibers in the vessel wall [4], thereby increasing aortic stiffness and decreasing vasoreactivity [5]. Additional reports show that connective tissue growth factor (CTGF), an established downstream mediator of TGFβ-induced fibrogenesis in mesenchymal cells [7], accumulate in thoracic aortic aneurysms and areas of dissection [8]. Another genetic polymorphism associated with increased risk of atherosclerosis, aortic aneurysms, and vascular dysfunction similar to Marfan syndrome is one affecting the LRP1 gene [9,10]. This gene encodes the LDL receptor related protein-1 (Lrp1) protein that has both cargo endocytosis and cell signal regulatory functions depending on the cell type involved [11]
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