Abstract
Our hypothesis was that overexpression of certain lipoprotein receptors might be related to lipid accumulation in the human ischemic myocardium. Intramyocardial lipid overload contributes to contractile dysfunction and arrhythmias in cardiomyopathy. Thus, the purpose of this study was to assess the effect of hypercholesterolemic LDL and hypertrigliceridemic VLDL dose on LRP1 expression in cardiomyocytes, as well as the potential correlation between LRP1 expression and neutral lipid accumulation in the left ventricle tissue from ischemic cardiomyopathy patients. Cell culture experiments include control and LRP1-deficient cardiomyocytes exposed to lipoproteins under normoxic and hypoxic conditions. Explanted hearts from 18 ICM patients and eight non-diseased hearts (CNT) were included. Low density lipoprotein receptor-related protein 1 (LRP1), very low density lipoprotein receptor (VLDLR) and low density lipoprotein receptor (LDLR) expression was analyzed by real time PCR and Western blotting. Cholesteryl ester (CE), triglyceride (TG) and free cholesterol (FC) content was assess by thin layer chromatography following lipid extraction. Western blotting experiments showed that protein levels of LRP1, VLDLR and HIF-1α were significantly upregulated in ischemic hearts. Immunohistochemistry and confocal microscopy analysis showed that LRP1 and HIF-1α were upregulated in cardiomyocytes of ICM patients. In vitro studies showed that VLDL, LDL and hypoxia exerted an upregulatory effect on LRP1 expression and that LRP1 played a major role in cholesteryl ester accumulation from lipoproteins in cardiomyocytes. Myocardial CE accumulation strongly correlated with LRP1 levels in ischemic hearts. Taken together, our results suggest that LRP1 upregulation is key for myocardial cholesterol ester accumulation in ischemic human hearts and that LRP1 may be a target to prevent the deleterious effects of myocardial cholesterol accumulation in ischemic cardiomyopathy.
Highlights
The ischemic condition caused by decreased coronary flow is one of the most important factors leading to heart failure
Taken together, our results demonstrate for the first time that myocardial lipoprotein receptor related protein 1 (LRP1) expression and cholesteryl ester content appear strongly increased and interrelated in the myocardium of ischemic cardiomyopathy patients
We show that LRP1 is upregulated in ischemic human hearts at mRNA and protein levels, to a different extent
Summary
The ischemic condition caused by decreased coronary flow is one of the most important factors leading to heart failure. The patients with fat deposition had larger infarctions, decreased wall thickening and impaired endocardial wall motion [4] It is known from several years ago that triglyceride (TG)-rich lipoproteins (chylomicrons and VLDL) supply both triglycerides and cholesteryl esters (CE) to the heart [13,14,15]. The upregulation of several lipoprotein receptors, including very low density lipoprotein receptor (VLDLR) [16] or low density lipoprotein receptor related protein 1 (LRP1) [17], has been previously reported to induce neutral lipid accumulation in cardiomyocytes under ischemic conditions Both VLDLR [16] and LRP1 [17,18] share a HIF-1α-dependent mechanism of transcriptional activation by hypoxia in cultured cells. LRP1 is upregulated by extracellular matrix-aggregated LDL in cultured human vascular smooth muscle cells and by hypercholesterolemia in the porcine vascular wall [19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
