Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus

Abstract

Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. Clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke and several mendelian traits featuring stroke have been described. The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes as well as an increased sensitivity to experimentally induced focal cerebral ischaemia. Rubattu et al. performed a genomewide screen in an F2 cross obtained by mating SHRSP and SHR, in which latency to stroke on Japanese rat diet was used as a phenotype. This study identified three major quantitative trait loci (QTLs), STR-1-3. Of these, STR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atrial natriuretic and brain natriuretic factors. Our investigation was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F2 cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 which accounts for 67% of the total variance, co-localizes with the genes encoding atrial and brain natriuretic factor and is blood pressure independent.

Microarray Analysis of Rat Chromosome 2 Congenic Strains

“…The SHRSP develops a number of vascular complications, including cardiac hypertrophy, cardiac failure, and stroke. [2][3][4] Genome-wide linkage studies have proved successful in the localization of large chromosomal regions containing quantitative trait loci (QTLs) for blood regulation in the SHRSP. 5 In particular, previous work in our laboratory has identified at least 2 blood pressure QTLs mapping to rat chromosome 2.…”

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

“…Both studies indicated that the QTLs identified affected the stroke-related phenotypes independently of BP. Although the atrial natriuretic peptide gene was focused on in the Chr 5 QTL, 37,38 further studies on this gene and genes in other QTLs have not yet been performed.…”

“…Rubattu et al 35,36 identified QTLs for stroke latency on Chr 1, 4 and 5 in an F2 intercross between SHRSP/Bbb and SHR/Bbb, of which the QTL on Chr 1 was confirmed in congenic strains. A QTL analysis in an F2 cross between SHRSP/Gcrc and WKY/Gcrc by Jeff et al 37 showed a strong linkage of the markers on Chr 5 with the infarction volume after middle cerebral artery occlusion. Both studies indicated that the QTLs identified affected the stroke-related phenotypes independently of BP.…”

Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control

“…The rat is an important model system for the development of cardiovascular gene therapy, for example, endothelial cell dysfunction associated with hypertension, left ventricular hypertrophy and stroke. [19][20][21] Importantly, transduction of rat arteries is relatively poor using nonmodified vectors and high titers are required. [22][23][24] We compared transduction evoked by AdCMV.luc with AdFLT-1.luc (Figure 2a).…”