PAC1 deficiency attenuates progression of atherosclerosis in ApoE deficient mice under cholesterol-enriched diet

Splitthoff, Paul; Rasbach, Erik; Neudert, Philip; Bonaterra, Gabriel A.; Schwarz, Anja; Mey, Lilli; Schwarzbach, Hans; Eiden, Lee E.; Weihe, Eberhard; Kinscherf, Ralf

doi:10.1016/j.imbio.2020.151930

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…Interestingly, in spite of the several reported protective effects of the PAC1 receptor, PAC1 receptor deficiency has been found to attenuate progression of atherosclerosis in apolipoprotein E-deficient mice [31]. There are other controversial data on PAC1 deficiency.…”

Section: Discussionmentioning

confidence: 99%

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Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

et al. 2021

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Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with widespread expression and general cytoprotective effects, is also involved in aging. Previously, we observed accelerated systemic senile amyloidosis in PACAP knockout (KO) mice. As mice partially lacking PACAP (heterozygous-HZ) show variable symptoms, here we investigated whether HZ mice have accelerated aging, completed with observations in PAC1 receptor KO mice. As we have limited data on qualitative or quantitative changes in the blood of PACAP-deficient mice, we investigated whether these changes could be in the background of the amyloidosis. Routine histological staining was used to examine amyloid deposits, rated on a severity scale 0–3. Blood was collected from PACAP wild type/HZ mice for complete blood analysis. In contrast to receptor KO mice showing no amyloidosis, histopathological analysis revealed severe deposits in PACAP HZ mice, with kidney, spleen, skin, and intestines being most affected. Increased cholesterol, lipoprotein levels, and differences in several blood count parameters were found in HZ mice. In summary, amyloidosis also develops in partial absence of PACAP, in contrast to the lack of its PAC1 receptor. In addition to the earlier identified inflammatory and degenerative disturbances, the alteration in lipid metabolism and bone marrow activity can also be additional factors leading to systemic degenerative processes.

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Section: Discussionmentioning

confidence: 99%

“…Much less is known about mice lacking the specific receptor of PACAP (PAC1 receptor). Some studies have been published on altered physiological and pathological reactions of these mice, but it is not known whether they show any aging-related signs [30,31].…”

Section: Introductionmentioning

confidence: 99%

Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

et al. 2021

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Functional Chemoanatomy of PACAP in Neuroendocrine and Neuronal Circuits

Eiden

Hernández

Jiang

et al. 2021

Masterclass in Neuroendocrinology

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

Blümm,

Bonaterra,

Schwarzbach

et al. 2023

BMC Cardiovasc Disord

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Background 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. Methods 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. Results 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. Conclusions 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.

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PAC1 deficiency attenuates progression of atherosclerosis in ApoE deficient mice under cholesterol-enriched diet

Cited by 4 publications

References 42 publications

Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

Functional Chemoanatomy of PACAP in Neuroendocrine and Neuronal Circuits

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

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