title: Augmented rififylin is a risk factor linked to aberrant cardiomyocyte function, short-QT interval and hypertension.
abstract: Using congenic strains of the Dahl salt-sensitive (S) rat introgressed with genomic segments from the normotensive Lewis rat, a blood pressure quantitative trait locus was previously mapped within 104 kb on chromosome 10. The goal of the current study was to conduct extensive phenotypic studies and to further fine-map this locus. At 14 weeks of age, the blood pressure of the congenic rats fed a low-salt diet was significantly higher by 47 mm Hg (P<0.001) compared with that of the S rat. A time-course study showed that the blood pressure effect was significant from very young ages of 50 to 52 days (13 mm Hg; P<0.01). The congenic strain implanted with electrocardiography transmitters demonstrated shorter-QT intervals and increased heart rate compared with S rats (P<0.01). The average survival of the congenic strain was shorter (134 days) compared with the S rat (175 days; P<0.0007). The critical region was narrowed to <42.5 kb containing 171 variants and a single gene, rififylin. Both the mRNA and protein levels of rififylin were significantly higher in the hearts of the congenic strain. Overexpression of rififylin is known to delay endocytic recycling. Endocytic recycling of fluorescently labeled holotransferrin from cardiomyocytes of the congenic strain was slower than that of S rats (P<0.01). Frequency of cardiomyocyte beats in the congenic strain (62±9 bpm) was significantly higher than that of the S rat (24±6 bpm; P<0.001). Taken together, our study provides evidence to suggest that early perturbations in endocytic recycling caused by the overexpression of Rffl is a novel physiological mechanism potentially underlying the development of hypertension.
authors.affiliation: Physiological Genomics Laboratory, Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Ave, Toledo, OH 43614-2598, USA.
authors.forename: Kathirvel
authors.initials: K
authors.lastname: Gopalakrishnan
authors.forename: Eric E
authors.initials: EE
authors.lastname: Morgan
authors.forename: Shane
authors.initials: S
authors.lastname: Yerga-Woolwine
authors.forename: Phyllis
authors.initials: P
authors.lastname: Farms
authors.forename: Sivarajan
authors.initials: S
authors.lastname: Kumarasamy
authors.forename: Andrea
authors.initials: A
authors.lastname: Kalinoski
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.forename: Bina
authors.initials: B
authors.lastname: Joe
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001794:Blood Pressure / Q000235:genetics*; D015153:Blotting, Western; D002874:Chromosome Mapping; D004452:Echocardiography; D015716:Electrocardiography, Ambulatory; D020869:Gene Expression Profiling; D006321:Heart / Q000502:physiology*; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D040641:Quantitative Trait Loci; D051381:Rats; D020303:Rats, Inbred Dahl; D011917:Rats, Inbred Lew; D044767:Ubiquitin-Protein Ligases
chemical_list: D051017:Apoptosis Regulatory Proteins; D011506:Proteins; C502761:Rffl protein, mouse; D044767:Ubiquitin-Protein Ligases