Overexpression of coupling factor 6 causes cardiac dysfunction under high-salt diet in mice.

Abstract

OBJECTIVE:

Reactive oxygen species are involved in the pathogenesis of congestive heart failure. We recently showed that coupling factor 6, a component of adenosine trisphosphate (ATP) synthase, induces hypertension by intracellular acidosis, which is related to reactive oxygen species generation. We investigated the effect of high-salt diet on the cardiac performance and reactive oxygen species generation in coupling factor 6-overexpressing transgenic mice.

METHODS AND RESULTS:

Baseline echocardiographic findings, reactive oxygen species generation, protein expression of sarcoplasmic/endoplasmic reticulum of Ca-ATPase 2 and phospholamban, and ATP content in the heart were similar between 7-week-old transgenic and wild-type mice. When the mice were fed with 8% salt diet for 20-24 weeks, fractional shortening of the left ventricle was decreased in transgenic mice compared with wild-type mice and was recovered by intraperitoneal administration of anticoupling factor 6 antibody. Nicotinamide adenine dinucleotide phosphate oxidase activity in the heart was increased in transgenic mice after the high-salt diet concomitantly with c-Src activation. The level of 8-iso-prostaglandin F2α was increased in transgenic heart compared with wild-type heart. The protein expression of sarcoplasmic/endoplasmic reticulum of Ca-ATPase 2 was decreased and that of phospholamban was increased in transgenic heart. In cDNA microarray analysis, the genes related to ATP synthesis and glycolysis were decreased in transgenic heart, concomitantly with the decrease in ATP content and the increase in β-myosin heavy chain.

CONCLUSION:

These suggest that coupling factor 6 induces the development of systolic dysfunction and upregulation of nicotinamide adenine dinucleotide phosphate oxidase in the heart under the high-salt diet.

• Authors: Toshihiro Ashitate, Tomohiro Osanai, Makoto Tanaka, Koji Magota, Takashi Echizen, Kei Izumiyama, Hiroaki Yokoyama, Shuji Shibutani, Kenji Hanada, Hirofumi Tomita, Ken Okumura
• Journal: Journal of hypertension (J Hypertens) Vol. 28 Issue 11 Pg. 2243-51 (Nov 2010) ISSN: 1473-5598 [Electronic] England
• PMID: 20811295 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Oxidative Phosphorylation Coupling Factors
• Reactive Oxygen Species
• Salts
• phospholamban
• 8-epi-prostaglandin F2alpha
• Calcitonin
• Dinoprost
• NADPH Oxidases
• F(6) ATPase
• Mitochondrial Proton-Translocating ATPases
• Calcium-Transporting ATPases

Topics

• Animals
• Calcitonin (chemistry)
• Calcium-Binding Proteins (genetics)
• Calcium-Transporting ATPases (genetics)
• Dinoprost (analogs & derivatives, genetics)
• Heart (physiology)
• Humans
• Mice
• Mice, Transgenic
• Mitochondrial Proton-Translocating ATPases (genetics, physiology)
• NADPH Oxidases (metabolism)
• Oligonucleotide Array Sequence Analysis
• Oxidative Phosphorylation Coupling Factors (genetics, physiology)
• Promoter Regions, Genetic
• Reactive Oxygen Species
• Salts (pharmacology)
• Systole