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.

METHODS AND 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: Po-Yin Chu, Amanda Zatta, Helen Kiriazis, Jaye Chin-Dusting, Xiao-Jun Du, Tanneale Marshall, David M Kaye
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 4 Issue 5 Pg. 651-8 (Sep 2011) ISSN: 1941-3297 [Electronic] United States
• PMID: 21685249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR4 protein, mouse
• Chemokine CXCL12
• Cxcl12 protein, mouse
• Mineralocorticoids
• N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine
• Pyridines
• Receptors, CXCR4
• Desoxycorticosterone

Topics

• Animals
• Chemokine CXCL12 (metabolism)
• Desoxycorticosterone (adverse effects, pharmacology)
• Disease Models, Animal
• Fibrosis
• Heart (drug effects)
• Hypertension (etiology, metabolism, prevention & control)
• Hypertrophy, Left Ventricular (etiology, metabolism, prevention & control)
• Kidney (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mineralocorticoids (adverse effects, pharmacology)
• Myocardium (metabolism, pathology)
• Pyridines (pharmacology)
• Receptors, CXCR4 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)