Abstract 564: Reduction of Blood Pressure with Antisense Oligodeoxynucleotides Against Chemerin
Chemerin promotes dendritic cells and macrophage migration to sites of inflammation. The liver and adipose tissues are sources of chemerin. There is a direct relationship of BMI, plasma chemerin concentration and blood pressure. Chemerin causes arterial contraction that is amplified in tissues with endothelial dysfunction. We hypothesized that if chemerin supported hypertension through such mechanisms, removal of chemerin should decrease blood pressure. Ten antisense oligodeoxynucleotides (ASOs) were developed against the retinoic acid receptor responder protein 2 (RARRES2, chemerin gene). ASO642647 was chosen as a lead based on excellent tolerance and minimal changes in a standard clinical panel. The model chosen was the deoxycorticosterone acetate (DOCA) salt hypertensive rat as this model shows profound endothelial dysfunction. Rats were uninephrectomized, given DOCA (s.c., 150 mg/kg) and placed on 1.0% NaCl + 0.2 % KCl. One week later, radiotelemeters were implanted for measurement of systolic, diastolic, mean arterial blood pressure and heart rate. ASOs (control nonsense or chemerin) were injected ip weekly over 3.5 weeks (25 mg/kg week 1 and 2; 12.5 mg/kg week 3 and 4) when DOCA-salt hypertension was stable (week 3.5). A group of DOCA-salt rats also received injections of PBS (ASO vehicle). Two days after the 4th injection, tissues were dissected for measurement of chemerin mRNA and blood taken for measures of catecholamines. ASO Chemerin reduced mean arterial blood pressure vs ASO control and PBS group within the first week, and remained reduced by ~17+/- 2 mm Hg at the time of sacrifice. Target organ mass (liver, heart and kidneys) was not different between ASO control and ASO chemerin group. HPLC revealed that circulating norepinephrine (NE) and dopamine (DA) were reduced 50% in the ASO chemerin vs control or PBS group. Real time RT-PCR validated knockdown of chemerin in ASO chemerin treated animals, with reductions as follows (vs ASO control, +/-3%): Liver (94%), epididymal fat (90%), retroperitoneal fat (90% ) and mesenteric perivascular adipose tissue (85%). These experiments provide powerful support for chemerin playing a role in blood pressure elevation.
Author Disclosures: B. Mahon: None. A. Mullick: A. Employment; Significant; AM employed at ISIS. F. Ownership Interest (includes any stock, stock option, partnership, membership or other equity position in an entity regardless of the form of the entity, or any option or right to acquire such position, and any rights in any patent or other intellectu; Significant; AM Ownership of ISIS stock. R. Burnett: None. S.W. Watts: None.
- © 2014 by American Heart Association, Inc.