Implication of chromosome 13 on hypertension and associated disorders in Lyon hypertensive rats.

BACKGROUND: Hypertension and associated disorders are major risk factors for cardiovascular disease. The Lyon hypertensive rat (LH) is a genetically hypertensive strain that exhibits spontaneous and salt-sensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia, and elevated insulin-to-glucose ratio. Previous genetic mapping identified quantitative trait loci (QTLs) influencing blood pressure (BP) on rat chromosome 13 (RNO13) in several models of hypertension. METHODS: To study the effects of a single chromosome on the mapped traits, we generated consomic strains by substituting LH RNO13 with that of the normotensive Brown Norway (BN) strain (LH-13BN) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13LH). These reciprocal consomic strains, as well as the two parental strains were characterized for BP, metabolic and morphological parameters. RESULTS: Compared with LH parents, LH-13BN rats showed decreased mean BP (up to -24 mmHg on 2% NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13LH and BN rats were much smaller than those observed between LH-13BN and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity was not affected by the substitution of RNO13, despite the significant BP differences. CONCLUSION: The present work demonstrates that RNO13 is a determinant of BP, proteinuria, and plasma lipids in the LH rat. The distinct phenotypic differences between the consomic LH-13BN and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease.

[Consomic approach to blood pressure and metabolic diseases in Lyon hypertensive rats]. / Approche consomique des troubles tensionnels et métaboliques du rat génétiquement hypertendu de souche lyonnaise (LH).

Genetically hypertensive rats of the Lyon strain (LH) have both high blood pressure and a metabolic syndrome. Linkage studies have disclosed quantitative trait loci of interest on chromosomes 2, 13 and 17. In the present work we designed consomic rats, i.e. LH rats in which a full chromosome was replaced by the same chromosome originating from the Brown-Norway (BN) normotensive strain. Rats consomic for chromosome 17 (LH-17BN) exhibited slightly but significantly lower blood pressure, which remained sensitive to an oral salt load. The cholesterol level was unaffected, while the triglyceride level was markedly depressed. This consomic approach seems to be of value for studying polygenic diseases such as hypertension and the metabolic syndrome. In the case of LH rats, our results confirm the functional importance of the loci identified on chromosome 17.

Reference signal extraction from corrupted ECG using wavelet decomposition for MRI sequence triggering: application to small animals.

BACKGROUND: Present developments in Nuclear Magnetic Resonance (NMR) imaging techniques strive for improved spatial and temporal resolution performances. However, trying to achieve the shortest gradient rising time with high intensity gradients has its drawbacks: It generates high amplitude noises that get superimposed on the simultaneously recorded electrophysiological signals, needed to synchronize moving organ images. Consequently, new strategies have to be developed for processing these collected signals during Magnetic Resonance Imaging (MRI) examinations. The aim of this work is to extract an efficient reference signal, from an electrocardiogram (ECG) that was contaminated by the NMR artefacts. This may be used for image triggering and/or cardiac rhythm monitoring. METHODS: Our method, based on sub-band decomposition using wavelet filters, is tested on various ECG signals recorded during three imaging sequences: Gradient Echo (GE), Fast Spin Echo (FSE) and Inversion Recovery with Spin Echo (IRSE). In order to define the most adapted wavelet functions to use according to the excitation protocols, noise generated by each imaging sequence is recorded and analysed. After exploring noise models along with information found in the literature, a group of 14 wavelets, members of three families (Daubechies, Coiflets, Symlets), is selected for the study. The extraction process is carried out by decomposing the contaminated ECG signals into 8 scales using a given wavelet function, then combining the sub-bands necessary for cardiac synchronization, i.e. those containing the essential part of the QRS energy, to construct a reference signal. RESULTS: The efficiency of the presented method has been tested on a group of quite representative signals containing: highly contaminated (mean SNR<--5 dB) simulated ECGs that replicate normal and pathological human heart beats, as well as some pathological and healthy rodents' actual ECG records. Despite the weak SNR of the contaminated ECG, the performances were quite satisfactory. When comparing the wavelet performances, one may notice that for a given sequence, some wavelets are more efficient for processing than others; for GE, FSE and IRSE sequence, good synchronisation condition is accomplished with coif5, sym8, and sym4 respectively. CONCLUSION: Sub-band decomposition proved to be very suitable for extracting a reference signal from a corrupted ECG for MRI triggering. An appropriate choice of the wavelet function, in accordance with the image sequence type, could considerably improve the quality of the reference signal for better image synchronization.

Effect of cholesteryl ester transfer protein (CETP) expression on diet-induced hyperlipidemias in transgenic rats.

OBJECTIVE: In order to determine the influence of the lipid status on the ability of cholesteryl ester transfer protein (CETP) to modify the plasma lipoprotein profile, the effect of hypercholesterolemia versus hypertriglyceridemia were compared in wild-type and CETP-transgenic (CETPTg) rats expressing CETP at a constant level. METHODS AND RESULTS: Wild-type and CETPTg rats were fed either a chow diet, a high fat/high cholesterol (HF/HC) diet, or a sucrose diet. As compared to wild-type rats, CETPTg rats fed the standard chow exhibited lower high-density lipoproteins (HDL)-cholesterol concentration (-65%, p<0.01), but similar non-HDL-cholesterol concentrations. Both wild-type and CETPTg rats fed the HF/HC diet displayed pronounced increases in total and non-HDL-cholesterol levels, with no influence of CETP expression in this case. In contrast, the sucrose diet produced significant changes only in CETPTg rats which then exhibited a 82% increase in non-HDL-cholesterol in addition to a 80% reduction in HDL cholesterol when compared to sucrose-fed, wild-type rats (p<0.01 in both cases). The triglyceride to cholesterol ratio in very low-density lipoprotein (VLDL) was 10-fold lower in 'HF/HC' rats than in 'chow' and 'sucrose' rats (p<0.005 and p<0.01, respectively), and VLDL from 'HF/HC' animals were proven to constitute poor cholesteryl ester acceptors. CONCLUSIONS: CETP expression modified dramatically the lipoprotein phenotype in 'sucrose' rats but not in 'HF/HC' rats. These observations suggest that a CETP inhibitor treatment is susceptible to produce profound changes in hypertriglyceridemia or combined hyperlipidemia.

Mapping the genetic determinants of hypertension, metabolic diseases, and related phenotypes in the lyon hypertensive rat.

The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat.

Expression of simian CETP in normolipidemic Fisher rats has a profound effect on large sized apoE-containing HDL.

In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P < 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P < 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P < 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.