Abstract 18096: Blood Pressure is Increased in Female Mice Lacking Orphan G Protein-Coupled Receptor Gpr37L1
Over 100 mammalian G protein-coupled receptors (GPCRs) are yet to be matched with endogenous ligands; these so-called ‘orphans’ offer hope as novel drug targets in the treatment of disease. One such orphan is GPR37L1; abundant in the brain and shown by our laboratory to be the first protease-inactivated GPCR. A previous study reports genetic deletion of GPR37L1 to cause hypertension and left ventricular hypertrophy (LVH) in mice.
Hypothesising that GPR37L1 is a cardiovascular regulator, we investigated the cardiovascular role of GPR37L1 using knockout and reporter mice. GPR37L1wt/wt (WT) and GPR37L1ko/ko (KO) mice were subject to blood pressure (BP) measurement by micromanometry, and LVH was assessed by morphometry and qPCR assays for induction of the fetal gene programme. Intriguingly, we report that the previously described hypertensive phenotype of KO mice is limited to females, which had significantly (p≤0.05) elevated systolic (+11.6 mmHg), diastolic and mean arterial pressures, relative to WT, with no difference in heart rate. Critically, we have validated this phenotype using radiotelemetry in conscious mice. Why the BP difference is sex-specific remains an interesting physiological question, while our ongoing investigation of the effects of angiotensin-II infusion in KO vs WT mice may unveil a BP/LVH phenotype in males.
In contrast to previous reports of GPR37L1 mRNA in heart/kidney, we could not detect the protein in either organ, using western blotting and microscopy of GPR37L1:lacZ tissue. We observed abundance of GPR37L1 in the brain, especially in astrocytes and Bergmann glia. This expression pattern suggests GPR37L1 to be a central mediator of BP and our ongoing RNA-seq studies aim to unveil this mechanism by identifying genes differentially expressed following GPR37L1 deletion. Our findings suggest GPR37L1 to be a hitherto unknown contributor to central BP regulation and intrinsic sex differences in BP.
Author Disclosures: J.L. Coleman: None. M.A. Mouat: None. J. Wu: None. N. Jancovski: None. D.T. Humphreys: None. M. Stefani: None. C.G. Dos Remedios: None. M.P. Feneley: None. A.M. Allen: None. R.M. Graham: None. N.J. Smith: None.
- © 2016 by American Heart Association, Inc.