Alterations in contractile protein composition and function in human atrial dilatation and atrial fibrillation

In humans, a low HDL concentration is one of the strongest indicators of increased risk for coronary heart disease. Apolipoprotein A-I (apo A-I) synthetic defects results in extremely low HDL levels and are frequently although not invariably associated with premature atherosclerosis. To investigate atherosclerosis susceptibility associated with HDL deficiency alone and in combination with other risk factors, such as high levels of LDL, we have quantified diet-induced atherogenesis in a series of genetically engineered mice, including mice with low HDL levels due to targeted disruption of both apo A-I alleles (AI KO mice), mice with high LDL levels due to expression of a human apolipoprotein B transgene (Btg mice), and mice with combined high LDL and low HDL levels due to the presence of the human apo B transgene and apo A-I knockout alleles, respectively (AI KO/Btg mice). After exposure to an atherogenic diet, AI KO and control mice had negligible lesions. All mice expressing the apo B transgene developed extensive lesions, but AI KO/Btg mice developed significantly larger lesions than Btg mice: 56, 260 +/- 4630 micron 2 for AI KO/Btg (n = 27) versus 38, 120 +/- 3350 micron 2 for Btg mice (n = 19) (P < .02). Results of this study, consistent with several human epidemiological studies, indicate that HDL deficiency in the mouse does not by itself lead to the development of atherosclerosis but does increase atherosclerosis susceptibility when accompanied by other risk factors, in this case elevated LDL.

HDL deficiency in genetically engineered mice requires elevatedLDL to accelerate atherogenesis

Apolipoprotein AI could be a significant determinant of epithelial integrity in rainbow trout gill cell cultures: a study in functional proteomics.

Background In chronic heart failure due to a dilated cardiomyopathy phenotype, the molecular bases for contractile dysfunction and chamber remodeling remain largely unidentified. Methods To investigate the feasibility of measuring global gene expression serially in the intact failing human heart, we performed repeated messenger RNA (mRNA) expression profiling using RNA extracted from endomyocardial biopsy specimens and gene chip methodology in 8 subjects with idiopathic dilated cardiomyopathy. In patients treated with β-blocking agents or placebo, myocardial gene expression was measured in endomyocardial biopsy material and radionuclide ejection fraction was measured at baseline and after 4 to 12 months of treatment. Gene expression was measured for 12,625 gene sequences by using Affymetrix U95 gene chips and commercially available software. For 6 mRNAs, gene chip results were compared with measurements made by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Results In an unfiltered composite analysis of changes in expression detected in the patients with high-signal intensity chips, 241 genes showed an increase and 331 genes a decrease in mRNA abundance. There was good agreement between changes measured by quantitative RT-PCR and those determined by gene chips. There was less variance between differences in phenotype in patients sampled serially as compared between subjects with similar phenotypes sampled at baseline. Conclusions Serial gene expression profiling with association to phenotypic change is feasible in the intact human heart and may offer advantages to cross-sectional expression profiling. This study suggests that the intact failing remodeled human heart is in an activated state of gene expression, with a large net reduction in gene expression occurring as phenotypic improvement occurs.

/pdf/serial-gene-expression-profiling-in-the-intact-human-heart-1seynzgckt.pdf

Serial gene expression profiling in the intact human heart.

The cardioprotective effects of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (apoA-I) are well documented, but their effects in the direction of the cardiac differentiation of embryonic stem cells are unknown. We evaluated the effects of exogenous apoA-I expression on cardiac differentiation of ESCs and maturation of ESC-derived cardiomyocytes. We stably over-expressed full-length human apoA-I cDNA with lentivirus (LV)-mediated gene transfer in undifferentiated mouse ESCs and human induced pluripotent stem cells. Upon cardiac differentiation, we observed a significantly higher percentage of beating embryoid bodies, an increased number of cardiomyocytes as determined by flow cytometry, and expression of cardiac markers including α-myosin heavy chain, β-myosin heavy chain and myosin light chain 2 ventricular transcripts in LV-apoA-I transduced ESCs compared with control (LV-GFP). In the presence of noggin, a BMP4 antagonist, activation of BMP4-SMAD signaling cascade in apoA-I transduced ESCs completely abolished the apoA-I stimulated cardiac differentiation. Furthermore, co-application of recombinant apoA-I and BMP4 synergistically increased the percentage of beating EBs derived from untransduced D3 ESCs. These together suggests that that pro-cardiogenic apoA-I is mediated via the BMP4-SMAD signaling pathway. Functionally, cardiomyocytes derived from the apoA-I-transduced cells exhibited improved calcium handling properties in both non-caffeine and caffeine-induced calcium transient, suggesting that apoA-I plays a role in enhancing cardiac maturation. This increased cardiac differentiation and maturation has also been observed in human iPSCs, providing further evidence of the beneficial effects of apoA-I in promoting cardiac differentiation. In Conclusion, we present novel experimental evidence that apoA-I enhances cardiac differentiation of ESCs and iPSCs and promotes maturation of the calcium handling property of ESC-derived cardiomyocytes via the BMP4/SMAD signaling pathway.

/pdf/exogenous-expression-of-human-apoa-i-enhances-cardiac-12wld61qrj.pdf

Exogenous expression of human apoA-I enhances cardiac differentiation of pluripotent stem cells

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2803%2901429-7

Expression and secretion of human apolipoprotein A-I in the heart.

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Expression and secretion of human apolipoprotein A-I in the heart.