Pressure overload by suprarenal aortic constriction in mice leads to left ventricular hypertrophy without c-Kit expression in cardiomyocytes

Amy M Nicks,Michael P Feneley,Siiri E Iismaa,Robert M Graham,Ming Li,Nicola J Smith,Scott H Kesteven,Nawazish Naqvi,Ahsan Husain,Jianxin Wu,Andrea Y Chan

doi:10.1038/s41598-020-72273-3

Abstract

Animal models of pressure overload are valuable for understanding hypertensive heart disease. We characterised a surgical model of pressure overload-induced hypertrophy in C57BL/6J mice produced by suprarenal aortic constriction (SAC). Compared to sham controls, at one week post-SAC systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was evident by a 50% increase in the LV weight-to-tibia length ratio due to cardiomyocyte hypertrophy. As a result, LV end-diastolic wall thickness-to-chamber radius (h/R) ratio increased, consistent with the development of concentric hypertrophy. LV wall thickening was not sufficient to normalise LV wall stress, which also increased, resulting in LV systolic dysfunction with reductions in ejection fraction and fractional shortening, but no evidence of heart failure. Pathological LV remodelling was evident by the re-expression of fetal genes and coronary artery perivascular fibrosis, with ischaemia indicated by enhanced cardiomyocyte Hif1a expression. The expression of stem cell factor receptor, c-Kit, was low basally in cardiomyocytes and did not change following the development of robust hypertrophy, suggesting there is no role for cardiomyocyte c-Kit signalling in pathological LV remodelling following pressure overload.

Highlights

Animal models of pressure overload are valuable for understanding hypertensive heart disease
We show that despite suprarenal aortic constriction (SAC) resulting in the rapid onset of pressure overload (PO)-induced hypertension, which is associated with pathological cardiac hypertrophy, significant left ventricular (LV) wall stress, perivascular fibrosis and ischaemia, cardiomyocyte c-Kit expression is barely detectable before, and is unchanged after the development of PO
We demonstrated that LV growth in response to SAC was due to cardiomyocyte hypertrophy, evident by a 17% enlargement in cardiomyocyte area, with an increase in the end-diastolic LV wall thickening-to-chamber radius (h/R ratio); this is consistent with the development of concentric hypertrophy

Summary

Introduction

Animal models of pressure overload are valuable for understanding hypertensive heart disease. We characterised a surgical model of pressure overload-induced hypertrophy in C57BL/6J mice produced by suprarenal aortic constriction (SAC). The expression of stem cell factor receptor, c-Kit, was low basally in cardiomyocytes and did not change following the development of robust hypertrophy, suggesting there is no role for cardiomyocyte c-Kit signalling in pathological LV remodelling following pressure overload. Two commonly used cardiac injury models are myocardial infarction (MI) produced by ligation of the left anterior descending coronary artery, and aortic constriction; the latter first developed and characterised by Rytand[3] and Goldblatt et al.[4], produced by ligating the descending abdominal aorta between or immediately above the renal arteries. Constriction of the abdominal aorta induces PO leading to the rapid development of cardiac hypertrophy and heart failure[2,5]. The controversies surrounding cardiac c-Kit expression are complicated further by the use of many different genetically modified c-Kit mouse models, cardiac injury types, and methods used to identify cardiac cell populations, which have been extensively r eviewed[16,17]

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Results

Conclusion