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(Circulation. 2001;103:442.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

Evaluation of Cardiac Ryanodine Ryr2 Receptor as a Candidate

Lan Zhao, PhD; Abdelkrim Sebkhi, PhD; Derek J. R. Nunez, MD; Lu Long, PhD; Christopher S. Haley, PhD; Josiane Szpirer, PhD; Claude Szpirer, PhD; Alan J. Williams, PhD; Martin R. Wilkins, MD

From the Section on Clinical Pharmacology (L.Z., A.S., D.J.R.N., L.L., M.R.W.) and Cardiac Medicine (A.J.W.), National Heart and Lung Institute, Imperial College School of Science, Technology, and Medicine, London, UK; the Department of Genetics and Biometry (C.S.H.), Roslin Institute, Edinburgh, UK; and Université Libre de Bruxelles (J.S., C.S.), Institut de Biologie et de Médecine Moléculaires, Rue Profs Jeener et Brachet, Gosselies, Belgium.

Correspondence to Prof M.R. Wilkins, Section on Clinical Pharmacology, Hammersmith Hospital, Ducane Road, London W12 ONN, UK. E-mail m.wilkins{at}ic.ac.uk

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.

Methods and Results—Male F₂ offspring from an F344xWKY intercross were exposed to hypoxia (10% O₂) 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 F₂ 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. [³H]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.

Key Words: genetics • hypertrophy • hypoxia

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