Right ventricular hypertrophy secondary to pulmonary hypertension is linked to rat chromosome 17: evaluation of cardiac ryanodine Ryr2 receptor as a candidate.
BACKGROUND
Fischer 344 (F344) rats are relatively resistant to hypoxia-induced right ventricular (RV) hypertrophy compared with the Wistar-Kyoto (WKY) strain. These 2 strains were used to examine the genetic basis for the differential response.


RESULTS
Male F(2) offspring from an F344xWKY intercross were exposed to hypoxia (10% O(2)) for 3 weeks, and pulmonary artery pressure and cardiac chamber weights were measured. Genomic DNA was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). A quantitative trait locus (QTL) for RV weight was identified 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 pulmonary artery pressure. The peak was centered over marker D17Rat41, close to Chrm3, 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 ryanodine receptor, colocalizes with our QTL. A panel of somatic cell hybrids and fluorescence in situ hybridization mapped Ryr2 close to the gene Chrm3 within our QTL. [(3)H]Ryanodine binding to cardiac membranes from the parental strains showed a 21% reduction in B(max) in the WKY compared with the F344 strain, with no difference in K:(d).


CONCLUSIONS
These data provide the first demonstration of a QTL linked to the 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.
Zhao
L
L
Section on Clinical Pharmacology, National Heart and Lung Institute, Imperial College School of Science, Technology, and Medicine, London, UK.
Sebkhi
A
A
Nunez
D J
DJ
Long
L
L
Haley
C S
CS
Szpirer
J
J
Szpirer
C
C
Williams
A J
AJ
Wilkins
M R
MR
D000818:Animals; D001835:Body Weight; D002886:Chromosomes, Human, Pair 17; D003433:Crosses, Genetic; D008040:Genetic Linkage; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000209:etiology / Q000235:genetics; D017380:Hypertrophy, Right Ventricular / Q000150:complications* / Q000235:genetics; D000860:Hypoxia; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
D019837:Ryanodine Receptor Calcium Release Channel