Prolactin receptor antagonism uncouples lipids from atherosclerosis susceptibility

Abstract

The pituitary-derived hormone prolactin has been suggested to stimulate the development of atherosclerosis and cardiovascular disease through its effects on metabolism and inflammation. In this study, we aimed to challenge the hypothesis that inhibition of prolactin function may beneficially affect atherosclerosis burden. Hereto, atherosclerosissusceptible LDL receptor (Ldlr) knockout mice were transplanted with bone marrow from transgenic mice expressing the pure prolactin receptor antagonist Del1-9-G129R-hPRL or their non-transgenic littermates as control. Recipient mice expressing Del1-9-G129R-hPRL exhibited a decrease in plasma cholesterol levels (K29%; P!0.05) upon feeding a Westerntype diet (WTD), which could be attributed to a marked decrease (K47%; P!0.01) in the amount of cholesterol esters associated with pro-atherogenic lipoproteins VLDL/LDL. By contrast, Del1-9-G129R-hPRL-expressing mice did not display any change in the susceptibility for atherosclerosis after 12 weeks of WTD feeding. Both the absolute atherosclerotic lesion size (223G33!10 3 mm 2 for Del1-9-G129R-hPRL vs 259G32!10 3 mm 2 for controls) and the lesional macrophage and collagen contents were not different between the two groups of bone marrow recipients. Importantly, Del1-9-G129R-hPRL exposure increased levels of circulating neutrophils (C91%; P!0.05), lymphocytes (C55%; P!0.05), and monocytes (C43%; P!0.05), resulting in a 49% higher (P!0.01) total blood leukocyte count. In conclusion, we have shown that prolactin receptor signaling inhibition uncouples the plasma atherogenic index from atherosclerosis susceptibility in Ldlr knockout mice. Despite an associated decrease in VLDL/LDL cholesterol levels, application of the prolactin receptor antagonist Del1-9-G129R-hPRL does not alter the susceptibility for initial development of atherosclerotic lesions probably due to the parallel increase in circulating leukocyte concentrations. Key Words" prolactin receptor " Del1-9-G129R-hPRL

The role of prolactin/vasoinhibins in cardiovascular diseases

“… 58 Ronald J. van der Sluis et al induced long‐term receptor antagonist Del1‐9‐G129R‐hPRL in mice by bone marrow transplantation in irradiated atherosclerosis‐susceptible LDL receptor knockout mice and found blocking PRLR reduced the atherogenic index but had no effect on the initial development of atherosclerotic lesions. 59 Meanwhile, several in vitro studies indicated a direct effect of PRL on ECs, 57 smooth muscle cells, 49 fibroblasts, 34 and other cells, which eventually may lead to endothelial dysfunction, pathologic vascular tone, arterial stiffening, increased BP, and further end‐organ disease. 35 , 54 , 56 …”

“…Chang et al confirmed that a threefold increase in plasma PRLcould significantly increase BP and markedly impair cardiac function by the activation of eNOS and NO production 58. Ronald J. van der Sluis et al induced long-term receptor antagonist Del1-9-G129R-hPRL in mice by bone marrow transplantation in irradiated atherosclerosis-susceptible LDL receptor knockout mice and found blocking PRLR reduced the atherogenic index but had no effect on the initial development of atherosclerotic lesions 59. Meanwhile, several in vitro studies indicated a direct effect of PRL on ECs, 57 smooth muscle cells, 49 fibroblasts,34 and other cells, which eventually may lead to endothelial dysfunction, pathologic vascular tone, arterial stiffening, increased BP, and further endorgan disease.35,54,Peripartum cardiomyopathyPPCM is an idiopathic, multifactor cause of heart failure occurring at the end of pregnancy or in the first months after delivery; 23-kDa PRL and the production of a cleaved 16-kDa fragment of PRL have emerged as potential key factors in the pathophysiology of PPCM, 60 of which 16-kDa PRL serves as the main trigger of PPCM 61.…”