Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model.

Qifeng Zhou,Michael Gramlich,Michael P Feneley,Meinrad Gawaz,Richard P Harvey,Scott Kesteven,Parwez Aidery,Jianxin Wu

doi:10.1155/2015/163564

Abstract

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.

Highlights

Dilated cardiomyopathy (DCM), a heart disease that is characterized by left ventricular dilatation, reduction in left ventricular function, and occurrence of cardiac arrhythmias, is a major cause for congestive heart failure [1]
We have previously generated a mouse model that imitates a human truncation mutation we found in a large DCM pedigree
We showed that pressure overload by thoracic aortic constriction induces maladaptive hypertrophy with impaired left ventricular function in a mouse model with a TTN truncation mutation we found in a family with dilated cardiomyopathy

Summary

Introduction

Dilated cardiomyopathy (DCM), a heart disease that is characterized by left ventricular dilatation, reduction in left ventricular function, and occurrence of cardiac arrhythmias, is a major cause for congestive heart failure [1]. About 20–48% of DCM cases are inherited with mutations in a variety of genes encoding sarcomeric, cytoskeletal, and nuclear membrane proteins, as well as proteins involved in Ca2+ metabolism [2]. The sarcomeric protein titin (TTN) is the biggest known single-copy protein in humans, mainly expressed in muscle tissue [3]. A single TTN molecule spans half the sarcomere and links the Z-disc with the M-line. As a pivotal building block of the sarcomere, it provides passive forces and mainly contributes to the elasticity of a muscle [4]. TTN plays a major role in scaffolding and coordinating structural and signal proteins for mechanotransduction [5]

Methods

Results

Conclusion