Transgenic overexpression of pregnancy-associated plasma protein-A in murine arterial smooth muscle accelerates atherosclerotic lesion development

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) increases local IGF-I bioavailability through cleavage of inhibitory IGF binding protein (IGFBP)-4 in a variety of systems, including the cardiovascular system. To test the hypothesis that expression of PAPP-A promotes the development of atherosclerotic lesions, we generated transgenic mice that express human PAPP-A in arterial smooth muscle. Four founder lines were characterized for transgenic human PAPP-A mRNA and protein expression, IGFBP-4 protease activity, and tissue specificity. In study I, apolipoprotein E knockout (ApoE KO) mice, a well-characterized mouse model of atherosclerosis, and ApoE KO mice expressing the human PAPP-A transgene at relatively high levels (ApoE KO/Tg) were fed a high-fat diet. At harvest, aortas were dissected and opened longitudinally for en face staining of lipid-rich lesions. Lesion area was increased 3.5-fold in aortas from ApoE KO/Tg compared with ApoE KO mice (P < 0.001), but no significant difference was seen in lesion number. In study II, replacement of PAPP-A expression in arterial smooth muscle of double ApoE KO/PAPP-A KO mice resulted in a 2.5-fold increase in lesion area (P = 0.002), without an effect on lesion number. PAPP-A transgene expression was associated with a significant increase in an IGF-responsive gene (P < 0.001), suggesting increased local IGF-I action. We therefore conclude that expression of human PAPP-A localized to arterial smooth muscle accelerates lesion progression in a mouse model of atherosclerosis. These data provide further evidence for the importance of PAPP-A in the cardiovascular system and suggest PAPP-A as a potential therapeutic target in the control of atherosclerosis.

Molecular Biology of Atherosclerosis

“…However, excessive IGF-IR signaling may actually increase atherosclerosis as illustrated by studies of modified pregnancy-associated plasma protein A (PAPP-A) expression (350,722). PAPP-A is a metalloproteinase that degrades IGFBP-4 (IGF-I binding protein 4), thereby increasing local IGF-I availability and signaling.…”

Pregnancy-associated plasma protein A: spotlight on kidney diseases

“…In contrast, transgenic mice with over expression of PAPP-A in arterial smooth muscle show accelerated atherosclerotic lesion development (36) .…”

Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo

“…Development of founder lines of PAPP-A transgenic (Tg) mice on an FVB background was reported recently (9). PAPP-A Tg mice designated Tg-4= by Conover et al (9) were used for all experiments except for the comparison studies in Table 1, which also included Tg-6=.…”

“…Development of founder lines of PAPP-A transgenic (Tg) mice on an FVB background was reported recently (9). PAPP-A Tg mice designated Tg-4= by Conover et al (9) were used for all experiments except for the comparison studies in Table 1, which also included Tg-6=. Briefly, human PAPP-A transgene expression in arterial smooth muscle was driven by a minimal smooth muscle 22␣ (SM22␣) promoter mutated to delete a G/C rich region responsible for repression of transcription in the vascular injury response (25,29).…”