Key result
Ischemic cardiomyopathy is linked to ~5-fold higher myocardial LRP1 expression and increased cholesteryl ester accumulation.
Why the study?
Overexpression of lipoprotein receptors may be related to lipid accumulation in the human ischemic myocardium, contributing to contractile dysfunction and arrhythmias in cardiomyopathy.
Does LRP1 expression correlate with cholesteryl ester accumulation in the myocardium of ischemic cardiomyopathy patients?
Cross-Sectional (n=26)
Yes
Does LRP1 expression correlate with cholesteryl ester accumulation in the myocardium of ischemic cardiomyopathy patients?
Absolute Event Rate: 30.62% vs 5.92%
p-value: p=<0.05
LRP1 upregulation correlates with myocardial cholesterol ester accumulation in ischemic hearts, suggesting it as a potential therapeutic target to prevent lipid overload-induced dysfunction in ischemic cardiomyopathy.
May link hyperlipidemic LDL/VLDL to LRP1-driven lipid overload in ischemic myocardium; leaves open any therapeutic role pending prospective validation.
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.
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Cal et al. (2012) conducted a cross-sectional in Ischemic cardiomyopathy (n=26). Ischemic cardiomyopathy vs. Non-diseased donor hearts was evaluated on LRP1 protein expression (p=<0.05). Ischemic cardiomyopathy was associated with significantly higher myocardial LRP1 protein expression and cholesteryl ester content compared to controls, with a strong correlation between the two.
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