Aquaporin-1 Deficiency Protects Against Myocardial Infarction by Reducing Both Edema and Apoptosis in Mice.

Lihua Li,Yuanlin Song,Chenjuan Yao,Zhiyong Weng,Tonghui Ma

doi:10.1038/srep13807

Abstract

Many studies have determined that AQP1 plays an important role in edema formation and resolution in various tissues via water transport across the cell membrane. The aim of this research was to determine both if and how AQP1 is associated with cardiac ischemic injury, particularly the development of edema following myocardial infarction (MI). AQP1+/+ and AQP1−/− mice were used to create the MI model. Under physiological conditions, AQP1−/− mice develop normally; however, in the setting of MI, they exhibit cardioprotective properties, as shown by reduced cardiac infarct size determined via NBT staining, improved cardiac function determined via left ventricular catheter measurements, decreased AQP1-dependent myocardial edema determined via water content assays, and decreased apoptosis determined via TUNEL analysis. Cardiac ischemia caused by hypoxia secondary to AQP1 deficiency stabilized the expression of HIF-1α in endothelial cells and subsequently decreased microvascular permeability, resulting in the development of edema. The AQP1-dependent myocardial edema and apoptosis contributed to the development of MI. AQP1 deficiency protected cardiac function from ischemic injury following MI. Furthermore, AQP1 deficiency reduced microvascular permeability via the stabilization of HIF-1α levels in endothelial cells and decreased cellular apoptosis following MI.

Highlights

Myocardial infarction (MI) may result in myocardial edema, which is directly associated with mortality due to impairment in both left ventricular systolic and diastolic function[1,2,3]
We observed that AQP1 deficiency significantly decreased myocardial infarct size, and markedly reduced cardiac edema, stabilized hypoxia-inducible factor-1α (HIF-1α) levels and decreased both microvascular permeability and cellular apoptosis following myocardial infarction (MI), which may have been responsible for the improvements in the cardiac function of the AQP1 deficient mice
AQP1 immunohistochemistry staining demonstrated that the endothelial cells exhibited expression patterns consistent with those of normal human hearts and AQP1+/+ mouse hearts [Fig. 1(d)], as brown staining was visible across the membranes of the endothelial cells and limited staining of the myocytes was visible

Summary

Introduction

Myocardial infarction (MI) may result in myocardial edema, which is directly associated with mortality due to impairment in both left ventricular systolic and diastolic function[1,2,3]. Several studies involving AQP1 knockout mice have demonstrated that AQP1 is expressed in the microvasculature and the endothelium of cardiac tissue as determined via Western blotting and RT-PCR. (c) The RT-PCR (top) and Western blot (bottom) analyses demonstrate the relative expression levels of AQP1 in the AQP1−/− and AQP1+/+ mice hearts. We investigated the role of AQP1 following MI by comparing heart morphology, infarct size, myocardial water content, cardiac function and hypoxia-inducible factor-1α (HIF-1α ) levels and cellular apoptosis between AQP1−/− and AQP1+/+ mice. We observed that AQP1 deficiency significantly decreased myocardial infarct size, and markedly reduced cardiac edema, stabilized HIF-1α levels and decreased both microvascular permeability and cellular apoptosis following MI, which may have been responsible for the improvements in the cardiac function of the AQP1 deficient mice

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