Abstract 13835: Overexpression of Coupling Factor 6 Causes Salt-Sensitive Hypertension and Systolic Cardiac Dysfunction: Gender as an Important Modulator
Background: Coupling factor 6 (CF6), an endogenous prostacyclin inhibitor, induces tissue acidosis by activating the acid-loading transporter ecto-F1F0 complex, and suppresses nitric oxide generation. We recently showed that CF6 enhances reactive oxygen species (ROS) generation under a high salt diet in male mice, resulting in hypertension and systolic cardiac dysfunction. Age and gender are said to be related to the onset of salt-sensitive hypertension in humans, but its mechanism is poorly understood. Using a CF6-overexpressing transgenic mice (TG), we examined the influences of the age and gender to the onset of salt-sensitive hypertension and cardiac dysfunction mediated by CF6.
Methods and Results: Male and female wild type (WT) and TG mice at the age of 15 weeks were assigned to 4 groups: WT and TG fed with a normal- or a high-salt (8%) diet (n=5–6 in each group). Blood pressure, cardiac function, and ROS generation were monitored during 60-week period. In male mice, systolic blood pressure (SBP, mmHg) was first increased in TG at 20 weeks after initiation of high-salt diet compared with normal-salt diet (107±2 vs 118±2, p<0.05), but was not in WT. Being consistent with blood pressure elevation, fractional shortening of the left ventricle (LVFS, %) was decreased from 32.9±1.0 to 28.7±1.2 (p<0.05), and nicotinamide adenine dinucleotide phosphate oxidase activity and 8-iso-prostaglandin F2α level in the heart were increased by 24±8% and 83±31% (both p<0.05), respectively, in TG. These changes were abolished after intra-peritoneal administration of anti-CF6 antibody for 3 days. Until 60 weeks after initiation of high-salt diet, the changes observed in TG fed with high-salt diet were continued, but in WT, such changes were not observed. In female mice, the increase in SBP (105±2 vs 120±3, p<0.05) and the decrease in LVFS (34.2±1.7 vs 26.9±0.8, p<0.05) were first observed at 60 weeks after initiation of high-salt diet (after menopause) in TG, but was not in WT.
Conclusions: Overexpression of CF6 induced salt-sensitive hypertension complicating systolic dysfunction, but their onset was delayed in female mice, suggesting that female or male hormone may antagonize or promote the action of CF6 such as salt retention, ROS generation, and cardiac dysfunction.
- © 2010 by American Heart Association, Inc.