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PAC1 deficiency reduces chondrogenesis in atherosclerotic lesions of hypercholesterolemic ApoE-deficient mice. 2023

C Blümm, and G A Bonaterra, and H Schwarzbach, and L E Eiden, and E Weihe, and R Kinscherf
Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany.

Induction of chondrogenesis is associated with progressive atherosclerosis. Deficiency of the ADCYAP1 gene encoding pituitary adenylate cyclase-activating peptide (PACAP) aggravates atherosclerosis in ApoE deficient (ApoE-/-) mice. PACAP signaling regulates chondrogenesis and osteogenesis during cartilage and bone development. Therefore, this study aimed to decipher whether PACAP signaling is related to atherogenesis-related chondrogenesis in the ApoE-/- mouse model of atherosclerosis and under the influence of a high-fat diet. For this purpose, PACAP-/-/ApoE-/-, PAC1-/-/ApoE-/-, and ApoE-/- mice, as well as wildtype (WT) mice, were studied under standard chow (SC) or cholesterol-enriched diet (CED) for 20 weeks. The amount of cartilage matrix in atherosclerotic lesions of the brachiocephalic trunk (BT) with maximal lumen stenosis was monitored by alcian blue and collagen II staining on deparaffinized cross sections. The chondrogenic RUNX family transcription factor 2 (RUNX2), macrophages [(MΦ), Iba1+], and smooth muscle cells (SMC, sm-α-actin) were immunohistochemically analyzed and quantified. ApoE-/- mice fed either SC or CED revealed an increase of alcian blue-positive areas within the media compared to WT mice. PAC1-/-/ApoE-/- mice under CED showed a reduction in the alcian blue-positive plaque area in the BT compared to ApoE-/- mice. In contrast, PACAP deficiency in ApoE-/- mice did not affect the chondrogenic signature under either diet. Our data show that PAC1 deficiency reduces chondrogenesis in atherosclerotic plaques exclusively under conditions of CED-induced hypercholesterolemia. We conclude that CED-related chondrogenesis occurs in atherosclerotic plaques via transdifferentiation of SMCs and MΦ, partly depending on PACAP signaling through PAC1. Thus, PAC1 antagonists or PACAP agonists may offer therapeutic potential against pathological chondrogenesis in atherosclerotic lesions generated under hypercholesterolemic conditions, especially in familial hypercholesterolemia. This discovery opens therapeutic perspectives to be used in the treatment against the progression of atherosclerosis.

UI MeSH Term Description Entries
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D002784 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Epicholesterol
D000423 Alcian Blue A copper-containing dye used as a gelling agent for lubricants, for staining of bacteria and for the dyeing of histiocytes and fibroblasts in vivo. Alcian Blue 8GS,Alcian Blue 8GX,8GS, Alcian Blue,8GX, Alcian Blue,Blue 8GS, Alcian,Blue 8GX, Alcian,Blue, Alcian
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001057 Apolipoproteins E A class of protein components which can be found in several lipoproteins including HIGH-DENSITY LIPOPROTEINS; VERY-LOW-DENSITY LIPOPROTEINS; and CHYLOMICRONS. Synthesized in most organs, Apo E is important in the global transport of lipids and cholesterol throughout the body. Apo E is also a ligand for LDL receptors (RECEPTORS, LDL) that mediates the binding, internalization, and catabolism of lipoprotein particles in cells. There are several allelic isoforms (such as E2, E3, and E4). Deficiency or defects in Apo E are causes of HYPERLIPOPROTEINEMIA TYPE III. Apo-E,Apo E,Apo E Isoproteins,ApoE,Apolipoprotein E Isoproteins,Apoprotein (E),Apoproteins E,Isoproteins, Apo E,Isoproteins, Apolipoprotein E
D050197 Atherosclerosis A thickening and loss of elasticity of the walls of ARTERIES that occurs with formation of ATHEROSCLEROTIC PLAQUES within the ARTERIAL INTIMA. Atherogenesis,Atherogeneses,Atheroscleroses
D051219 Pituitary Adenylate Cyclase-Activating Polypeptide A multi-function neuropeptide that acts throughout the body by elevating intracellular cyclic AMP level via its interaction with PACAP RECEPTORS and VASOACTIVE INTESTINAL PEPTIDE RECEPTOR. Although first isolated from hypothalamic extracts and named for its action on the pituitary, it is widely distributed in the central and peripheral nervous systems. PACAP is important in the control of endocrine and homeostatic processes, such as secretion of pituitary and gut hormones and food intake. PACAP,PACAP-27,PACAP-38,PACAP27,PACAP38,Pituitary Adenylate Cyclase Activating Polypeptide,Pituitary Adenylate Cyclase Activating Polypeptide 27,Pituitary Adenylate Cyclase Activating Polypeptide 38
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D058226 Plaque, Atherosclerotic Lesions formed within the walls of ARTERIES associated with deposits of fat and other substances that accumulate in the lining of the artery wall. Atheromatous Plaque,Atheroma,Atheromatous Plaques,Atherosclerotic Plaque,Atherosclerotic Plaques,Fatty Streak, Arterial,Fibroatheroma,Fibroatheromatous Plaques,Arterial Fatty Streak,Arterial Fatty Streaks,Atheromas,Fibroatheromas,Fibroatheromatous Plaque,Plaque, Atheromatous,Plaque, Fibroatheromatous,Streak, Arterial Fatty
D059305 Diet, High-Fat Consumption of excessive DIETARY FATS. Diet, High Fat,Diets, High Fat,Diets, High-Fat,High Fat Diet,High Fat Diets,High-Fat Diet,High-Fat Diets

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