title: CXCR4 antagonism attenuates the cardiorenal consequences of mineralocorticoid excess.
abstract: BACKGROUND
  Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role.
  
  
  RESULTS
  We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg per day for 6 weeks through minipump) in dexoycorticosterone acetate (DOCA)-treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension, and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition.
  
  
  CONCLUSIONS
  Taken together, these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation, and cardiorenal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease.
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: Po-Yin
authors.initials: PY
authors.lastname: Chu
authors.forename: Amanda
authors.initials: A
authors.lastname: Zatta
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Jaye
authors.initials: J
authors.lastname: Chin-Dusting
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Tanneale
authors.initials: T
authors.lastname: Marshall
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism; D003900:Desoxycorticosterone / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008901:Mineralocorticoids / Q000009:adverse effects* / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008901:Mineralocorticoids; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; D003900:Desoxycorticosterone