Serum Proteomic Changes in Dogs with Different Stages of Chronic Heart Failure.

Ahmet Saril,Akiko Uemura,Zeki Yilmaz,Ryou Tanaka,Pinar Levent,Meric Kocaturk,Kazumi Shimada,Emel Akgün,Carlos Fernando Agudelo,Ahmet Tarik Baykal,Alberto Muñoz Prieto,Jorgen Koch,Jose Joaquin Ceron

doi:10.3390/ani12040490

Abstract

Simple SummaryCanine MMVD is a progressive chronic disease with variable clinical signs, with some patients remaining completely asymptomatic while others develop CHF. Here, the aims of the pilot study were to evaluate serum proteins by proteomic analysis in dogs at different stages of chronic heart failure (CHF) due to degenerative mitral valve disease (MMVD), and how these proteins can change after a conventional treatment. Study revealed 157 different proteins; 11 were up- and 21 down-regulated at a statistically significant level in dogs with CHF compared to controls. Based on the bioinformatic analysis, protein–protein interactions between complement proteins, fibrinogen subtypes and others (albumin precursor, serpins, inter-alpha-trypsin inhibitor heavy chain, fetuin, clusterin, apolipoproteins, and alpha-glycoproteins) showed that pathophysiology of CHF seems to be more sophisticated than we had thought. These proteins are associated with several cellular, biologic, and metabolic processes such as immune-inflammatory responses, hemostasis, oxidative stress, and energy metabolism, which might be detrimental in the progression of canine CHF. Their molecular and biological functions as well as roles in the signaling pathways, such as inflammation, cadherin signaling, nicotinic acetylcholine receptor signaling and Wnt signaling make them possible biomarkers and therapeutic targets for the diagnosis and treatments in dogs with different stages of CHF.MMVD, the most common cause of CHF in dogs, is a chronic disease with variable clinical signs, with some patients remaining asymptomatic while others develop CHF. Here, we aimed to evaluate serum proteins by proteomic analysis in dogs at different stages of CHF due to MMVD, and proteome behaviors after conventional treatment. A total of 32 dogs were divided equally into four groups—stage A (healthy/controls), stage B2 (asymptomatic), stage C and stage D (symptomatic)—according to the ACVIM consensus. Serum proteomes were evaluated using LC/MS-based label-free differential proteome analysis. The study revealed 157 different proteins; 11 were up- and 21 down-regulated in dogs with CHF compared to controls. In stage B2 dogs, angiotensinogen (AGT) was up-regulated, but immunoglobulin iota chain-like, lipopolysaccharide-binding protein, and carboxypeptidase (CPN) were down-regulated. In stage C dogs, complement C3 (C3) and inter-alpha-trypsin inhibitor heavy chain were up-regulated, but hemopexin, and actin-cytoplasmic-1 (ACT-1) were down-regulated. In stage D dogs, AGT was up-regulated, whereas tetranectin, paraoxonase-1, adiponectin and ACT-1 were down-regulated. A decrease in CPN, C3 and AGT and an increase in ACT-1 were observed after treatment of dogs in stage C. This pilot study identified that dogs at different stages of CHF show different serum protein composition which has potential to be biomarker for diagnose and treatment monitorization.

Highlights

Degenerative myxomatous mitral valve disease (MMVD) is the most common cause of chronic heart failure (CHF) in dogs
This study aimed to evaluate the composition of serum proteins by proteomics techniques at different stages of CHF due to MMVD in dogs, and how these proteins can change after conventional treatment
Groups of dogs used in this study were distinguished based on the results of physical, hematological and serum biochemistry examinations and cardiac imaging findings (Supplementary Files S1 and S2), which were compatible with the selection criteria for CHF from stages were compared to healthy control (stage A) to D described by ACVIM consensus guidelines for the diagnosis and treatment of MMVD in dogs [6]

Summary

Introduction

Degenerative myxomatous mitral valve disease (MMVD) is the most common cause of chronic heart failure (CHF) in dogs. The pathological changes give rise to mitral regurgitation leading to a gradually increasing chronic volume load on the left side of the heart, resulting in clinically detectable left atrial and/or left ventricular enlargement. In most of these dogs, the volume overload causes the development of signs of congestive heart failure such as pulmonary venous congestion and edema [4,5]. MMVD is a progressive chronic disease with variable clinical signs, with some patients remaining completely asymptomatic but others develop CHF. Depending on the presenting symptoms, MMVD has been staged from the initial step (stage A: healthy dogs with a genetic predisposition) to the terminal phase of CHF (stage D: refractory CHF) by the American College of Veterinary Internal Medicine (ACVIM, Greenwood Village, CO, USA) consensus statement [6]

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