title: Cardiac CRFR1 Expression Is Elevated in Human Heart Failure and Modulated by Genetic Variation and Alternative Splicing.
abstract: Corticotropin-releasing factor (CRF) and the CRF-related peptides, urocortin (Ucn)-1, Ucn2, and Ucn3 signal through receptors CRFR1 and CRFR2 to restore homeostasis in response to stress. The Ucns exert potent cardioprotective effects and may have clinical utility in heart failure. To explore the activity of this system in the heart, we measured the levels of myocardial gene expression of the CRF/Ucn family of ligands/receptors and investigated genetic variation and alternative splicing of CRFR1 in 110 heart failure patients and 108 heart donors. Using quantitative real-time PCR, we detected CRFR1, CRFR2, CRF, Ucn1, Ucn2, and Ucn3 in all samples. CRFR2α was the most abundant receptor and Ucn3 the most abundant ligand, both in patients and donors. Compared with donors, cardiac expression of CRFR1, CRF, and Ucn3 was higher (P < .001) and CRFR2α lower (P = .012) in patients. In patients and donors, genetic variation within CRFR1, represented by the chromosome 17q21.31 inversion polymorphism, was associated with markedly higher CRFR1 expression (P < .001), making CRFR1 and CRFR2α expression almost equivalent in some patients. A novel, truncated splice variant of CRFR1, designated CRFR1j, was identified and shown to exert a dominant-negative effect on CRFR1 signaling in vitro. The novel variant was expressed in a greater proportion of patients (60%) than donors (3%, P < .001). In summary, cardiac expression of CRFR1, CRF, and Ucn3 genes is elevated in heart failure and may contribute to the activation of the CRF/Ucn system in these patients. A common variant within the CRFR1 gene and a novel CRFR1 splice variant may modulate CRFR1 expression and signaling.
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Pilbrow
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Lewis
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Marilyn H
authors.initials: MH
authors.lastname: Perrin
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Sweet
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Moravec
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Huising
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Troughton
authors.affiliation: Peptide Biology Laboratories (A.P.P., K.A.L., M.H.P., M.O.H.), The Salk Institute for Biological Studies, La Jolla, California 92037; Christchurch Heart Institute (A.P.P., R.W.T., V.A.C.), Department of Medicine, University of Otago, Christchurch 8011, New Zealand; Kaufman Center for Heart Failure (W.E.S., C.S.M., W.H.W.T.), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Vicky A
authors.initials: VA
authors.lastname: Cameron
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D054832:Urocortins / Q000235:genetics / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; C576814:UCN protein, human; C426705:UCN2 protein, human; C426704:UCN3 protein, human; D054832:Urocortins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone