Abstract
Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in Apoe−/− and Ldlr−/− mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (Apoe−/− mice). Bone marrow from wild-type or Ldlr−/− mice was transplanted into irradiated Ldlr−/− recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in Apoe−/− and Ldlr−/− mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype.
Highlights
Hyperlipidemia is a well-established risk factor for cardiovascular diseases
Mean ± SEM (n = 6–15 animals/group). *P < 0.05, **P < 0.01 and ***P < 0.001 vs. wild-type (Mann–Whitney U test). (C) Platelet activation parameters were obtained from brightfield and fluorescence images after 3.5 min: P1, morphological score; P2, platelet surface area coverage (% SAC); P3, aggregate contraction score; P4, aggregate multilayer score; P5, aggregate multilayer coverage (% SAC); P6, PS exposure (% SAC); P7, P-selectin expression (% SAC); P8, integrin αIIbβ[3] activation (% SAC)
Much less is known about the effects of less aggressive forms of hyperlipidemia, that align with those seen in humans, on the thrombosis propensity and platelet activation
Summary
Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. We studied platelet activation and arterial thrombus formation in Apoe−/− and Ldlr−/− mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. The lipoprotein profile of Ldlr−/− mice resembles more that of human hypercholesterolemia, with cholesterol preferentially transported by low-density lipoproteins[12,13] Both knockouts develop progressive atherosclerosis of the aortic arch and carotid arteries, the precise mechanism differs between the g enotypes[10,14,15,16,17], in that atherosclerotic lesion formation upon LDLR deficiency more relies on the dietary fat content[11]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have