ABSTRACT
(1) Background: Apolipoprotein E (ApoE) is a critical plasma apolipoprotein for lipid transport and nonlipid-related functions. Humans possess three isoforms of ApoE (2, 3, and 4). ApoE2, which exhibits beneficial effects on cardiac health, has not been adequately studied. (2) Methods: We investigated the cardiac phenotypes of the humanized ApoE knock-in (hApoE KI) rats and compared to wild-type (WT) and ApoE knock-out (ApoE KO) rats using echocardiography, ultrasound, blood pressure measurements, histology strategies, cell culture, Seahorse XF, cardiomyocyte contractility and intracellular Ca2+ tests, and Western blotting; (3) Results: hApoE2 rats exhibited enhanced heart contractile function without signs of detrimental remodeling. Isolated adult hApoE2 cardiomyocytes had faster and stronger sarcomere contractility because of more mitochondrial energy generation and stimulation-induced fast and elevated intracellular Ca2+ transient. The abundant energy is a result of elevated mitochondrial function via fatty acid ß-oxidation. The fast and elevated Ca2+ transient is associated with decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2) and increased expression of cardiac ryanodine receptor 2 (RyR2) conducting a potent Ca2+ release from SR.; (4) Conclusions: Our studies validated the association of polymorphic ApoEs with cardiac health in the rat model, and revealed the possible mechanisms of the protective effect of ApoE2 against heart diseases.
Subject(s)
Myocytes, Cardiac , Sarcoplasmic Reticulum , Rats , Humans , Animals , Myocytes, Cardiac/metabolism , Apolipoprotein E2/metabolism , Apolipoprotein E2/pharmacology , Sarcoplasmic Reticulum/metabolism , EchocardiographyABSTRACT
Cadmium (Cd) exposure is associated with increased Alzheimer's disease (AD) risks. The human Apolipoprotein E (ApoE) gene encodes a lipid-transporting protein that is critical for brain functions. Compared with ApoE2 and E3, ApoE4 is associated with increased AD risk. Xenobiotic biotransformation-related genes have been implicated in the pathogenesis of AD. However, little is known about the effects of Cd, ApoE, and sex on drug-processing genes. We investigated the Cd-ApoE interaction on the transcriptomic changes in the brains and livers of ApoE3/ApoE4 transgenic mice. Cd disrupts the transcriptomes of transporter and drug-processing genes in brain and liver in a sex- and ApoE-genotype-specific manner. Proinflammation related genes were enriched in livers of Cd-exposed ApoE4 males, whereas circadian rhythm and lipid metabolism related genes were enriched in livers of Cd-exposed ApoE3 females. In brains, Cd up-regulated the arachidonic acid-metabolizing Cyp2j isoforms only in the brains of ApoE3 mice, whereas the dysregulation of cation transporters was male-specific. In livers, several direct target genes of the major xenobiotic-sensing nuclear receptor pregnane X receptor were uniquely upregulated in Cd-exposed ApoE4 males. There was a female-specific hepatic upregulation of the steroid hormone-metabolizing Cyp2 isoforms and the bile acid synthetic enzyme Cyp7a1 by Cd exposure. The dysregulated liver transporters were mostly involved in intermediary metabolism, with the most significant response observed in ApoE3 females. In conclusion, Cd dysregulated the brain and liver drug-processing genes in a sex- and ApoE-genotype specific manner, and this may serve as a contributing factor for the variance in the susceptibility to Cd neurotoxicity. SIGNIFICANCE STATEMENT: Xenobiotic biotransformation plays an important role in modulating the toxicity of environmental pollutants. The human ApoE4 allele is the strongest genetic risk factor for AD, and cadmium (Cd) is increasingly recognized as an environmental factor of AD. Very little is known regarding the interactions between Cd exposure, sex, and the genes involved in xenobiotic biotransformation in brain and liver. The present study has addressed this critical knowledge gap.
Subject(s)
Alzheimer Disease , Environmental Pollutants , Alzheimer Disease/chemically induced , Alzheimer Disease/genetics , Animals , Apolipoprotein E2/genetics , Apolipoprotein E2/metabolism , Apolipoprotein E2/pharmacology , Apolipoprotein E3/genetics , Apolipoprotein E3/metabolism , Apolipoprotein E3/pharmacology , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Apolipoprotein E4/pharmacology , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Apolipoproteins E/pharmacology , Arachidonic Acid/metabolism , Bile Acids and Salts/metabolism , Brain/metabolism , Cadmium/toxicity , Environmental Pollutants/metabolism , Female , Genetic Predisposition to Disease , Hormones/metabolism , Hormones/pharmacology , Humans , Liver/metabolism , Male , Mice , Mice, Transgenic , Pregnane X Receptor/metabolism , Protein Isoforms/metabolism , Xenobiotics/metabolismABSTRACT
The epsilon4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-beta (Abeta) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE-/- mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic Abeta42 in APOE epsilon2, epsilon3, and epsilon4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does influence the rate at which the mice are able to clear Abeta42 from their bloodstream. Both APOE epsilon4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Abeta42 over time compared to APOE epsilon2/APOE knock-out rE2 and APOE epsilon3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Abeta42 is significantly altered by APOE genotype. Given that APOE epsilon4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Abeta which may impact on clearance from the brain.
