Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor γ coactivator levels and mitochondrial dysfunction.
OBJECTIVE
Mitochondrial dysfunction has been suggested as a potential cause for heart failure. Pressure overload is a common cause for heart failure. However, implementing pressure overload in mice is considered a model for compensated hypertrophy but not for heart failure. We assessed the suitability of minimally invasive transverse aortic constriction to induce heart failure in C57BL/6 mice and assessed mitochondrial biogenesis and function.


METHODS
Minimally invasive transverse aortic constriction was performed through a ministernotomy without intubation (minimally invasive transverse aortic constriction, n = 68; sham operation, n = 43). Hypertrophy was assessed based on heart weight/body weight ratios and histologic analyses, and contractile function was assessed based on intracardiac Millar pressure measurements. Expression of selected metabolic genes was assessed with reverse transcription-polymerase chain reaction and Western blotting. Maximal respiratory capacity (state 3) of isolated mitochondria was measured with a Clark-type electrode.


RESULTS
Survival was 62%. Within 7 weeks, minimally invasive transverse aortic constriction induced significant hypertrophy (heart weight/body weight ratio: 10.08±0.28 mg/g for minimally invasive transverse aortic constriction vs 4.66±0.07 mg/g for sham operation; n=68; P<.01). Fifty-seven percent of mice undergoing minimally invasive transverse aortic constriction displayed signs of heart failure (pleural effusions, dyspnea, weight loss, and dp/dtmax of 3114±422 mm Hg/s, P<.05). All of them had heart weight/body weight ratios of greater than 10. Mice undergoing minimally invasive transverse aortic constriction with heart weight/body weight ratios of less than 10 had normal contractile function (dp/dtmax of 6471±292 mm Hg/s vs dp/dtmax of 6933±205 mmHg/s in sham mice) and no clinical signs of heart failure. The mitochondrial coactivator peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α) was downregulated in failing hearts only. PGC-1α and fatty acid oxidation gene expression were also decreased in failing hearts. State 3 respiration of isolated mitochondria was significantly reduced in all hearts subjected to pressure overload.


CONCLUSIONS
Contractile dysfunction and heart failure can be induced in wild-type mice by means of minimally invasive aortic constriction. Pressure overload-induced heart failure in mice is associated with mitochondrial dysfunction, as characterized by downregulation of PGC-1α and reduced oxidative capacity.
Faerber
Gloria
G
Department of Cardiac Surgery, University of Leipzig Heart Center, Leipzig, Germany.
Barreto-Perreia
Frederico
F
Schoepe
Maria
M
Gilsbach
Ralf
R
Schrepper
Andrea
A
Schwarzer
Michael
M
Mohr
Friedrich W
FW
Hein
Lutz
L
Doenst
Torsten
T
D000818:Animals; D001011:Aorta / Q000503:physiopathology / Q000601:surgery*; D001794:Blood Pressure; D015153:Blotting, Western; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019069:Cell Respiration / Q000235:genetics; D003250:Constriction; D004195:Disease Models, Animal; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017736:Ion-Selective Electrodes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019060:Minimally Invasive Surgical Procedures; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056346:Sternotomy; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014656:Vascular Surgical Procedures; D017725:Ventricular Pressure
D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors