Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model.
Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygous Ttn knock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC) in heterozygous (Het) Ttn knock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction (p < 0.05), while wild-type (WT) TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure.
Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
Qifeng
Q
Zhou
Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
Scott
S
Kesteven
Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
Jianxin
J
Wu
Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
Parwez
P
Aidery
Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany.
Meinrad
M
Gawaz
Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany ; Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
Michael
M
Gramlich
Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia ; St. Vincent's Clinical School, University of New South Wales, Kensington, NSW 2010, Australia ; Cardiology Department, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
Michael P
MP
Feneley
Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia ; St. Vincent's Clinical School, University of New South Wales, Kensington, NSW 2010, Australia ; School of Biological and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2010, Australia.
Richard P
RP
Harvey
D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques / Q000379:methods; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011494:Protein Kinases / Q000235:genetics*; D014463:Ultrasonography
D011494:Protein Kinases; C579730:titin protein, mouse