Right ventricular hypertrophy secondary to pulmonary hypertension is linked to rat chromosome 17 - Evaluation of cardiac ryanodine Ryr2 receptor as acandidate

Background-Fischer 344 (F344) rats are relatively resistant to hypoxia-indu ced right ventricular (RV) hypertrophy compared with the Wistar-Kyoto (WKY) strain. These 2 strains were used to examine the genetic basis for the dif ferential response. Methods and Results-Male F-2 offspring from an F344xWKY intercross were exp osed to hypoxia (10% O-2) for 3 weeks, and pulmonary artery pressure and ca rdiac chamber weights \vere measured. Genomic DNA was screened by use of po lymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). A quantitative trait locus (QTL) for RV weight was identifie d on rat chromosome 17 (lod score 6.5) that accounted for 22% of the total variance of RV weight in the F-2 population and was independent of pulmonar y artery pressure. The peak was centered over marker D17Rat41, close to Chr m3, with a 1-lod support interval of 5 cM. Comparison of homologous regions in mice and humans suggested that Ryr2, the cardiac isoform of the ryanodi ne receptor, colocalizes with our QTL, A panel of somatic cell hybrids and fluorescence in situ hybridization mapped Ryr2 close to the gene Chrm3 with in our QTL, [H-3]Ryanodine binding to cardiac membranes from the parental s trains showed a 21% reduction in B-max in the WKY compared with the F344 st rain, with no difference in K-d. Conclusions-These data provide the first demonstration of a QTL linked to t he RV response to hypoxia-induced pulmonary hypertension. The Ryr2 receptor gene lies within this QTL and merits further investigation as a candidate for this differential RV response.