Proteomic analysis of pulmonary arteries and lung tissues from dogs affected with pulmonary hypertension secondary to degenerative mitral valve disease

Abstract

In dogs with degenerative mitral valve disease (DMVD), pulmonary hypertension (PH) is a common complication characterized by abnormally elevated pulmonary arterial pressure (PAP). Pulmonary arterial remodeling is the histopathological changes of pulmonary artery that has been recognized in PH. The underlying mechanisms that cause this arterial remodeling are poorly understood. This study aimed to perform shotgun proteomics to investigate changes in protein expression in pulmonary arteries and lung tissues of DMVD dogs with PH compared to normal control dogs and DMVD dogs without PH. Tissue samples were collected from the carcasses of 22 small-sized breed dogs and divided into three groups: control (n = 7), DMVD (n = 7) and DMVD+PH groups (n = 8). Differentially expressed proteins were identified, and top three upregulated and downregulated proteins in the pulmonary arteries of DMVD dogs with PH including SIK family kinase 3 (SIK3), Collagen type I alpha 1 chain (COL1A1), Transforming growth factor alpha (TGF-α), Apoptosis associated tyrosine kinase (AATYK), Hepatocyte growth factor activator (HGFA) and Tyrosine-protein phosphatase non-receptor type 13 (PTPN13) were chosen. Results showed that some of the identified proteins may play a role in the pathogenesis of pulmonary arterial remodeling. This study concluded shotgun proteomics has potential as a tool for exploring candidate proteins associated with the pathogenesis of PH secondary to DMVD in dogs.

Pulmonary Hypertension Secondary to Myxomatous Mitral Valve Disease in Dogs: Current Insights into the Histological Manifestation and Its Determining Factors

“…It has been indicated that the appearance of PVH in dogs with left heart failure leads to a significant decrease in the synthesis of bcl-2-like protein 4 (BAX), caspase-3, and caspase-8 proteins (pro-apoptotic proteins) and an increase in the expression of anti-apoptotic B-cell lymphoma-2 (BCL-2) [45]. Proteomic studies, in dogs with MMVD and PVH, revealed an increase in the synthesis of apoptosis resistance proteins and the progression of medial thickening [57]. The study detected the proteins whose changes were most significant: up-regulation of salt-induced kinase 3 (SIK3), collagen type I alpha chain 1 (COL1A1), and transforming growth factor alpha (TGF-α) and down-regulation of apoptosis-associated tyrosine kinase (AATYK), hepatocyte growth factor activator (HGFA) and non-receptor protein tyrosine phosphatase type 13 (PTPN13) [57].…”

“…Proteomic studies, in dogs with MMVD and PVH, revealed an increase in the synthesis of apoptosis resistance proteins and the progression of medial thickening [57]. The study detected the proteins whose changes were most significant: up-regulation of salt-induced kinase 3 (SIK3), collagen type I alpha chain 1 (COL1A1), and transforming growth factor alpha (TGF-α) and down-regulation of apoptosis-associated tyrosine kinase (AATYK), hepatocyte growth factor activator (HGFA) and non-receptor protein tyrosine phosphatase type 13 (PTPN13) [57]. The SIK family of proteins is one of the regulators of myocardial inflammation and fibrosis through the activation of apoptosis signal-regulating kinase 1 (ASK1) [58,59].…”

“…Stimulation of growth factor activation also occurs in tumor cells, which are known to have impaired apoptosis processes, which may account for the higher TGF-α activity in vessel wall cells [60]. Interestingly, differences between the pulmonary artery and peripheral pulmonary arteries were indicated in terms of which proteins were synthesized the most [57]. One study showed a difference in the expression of DNA-binding inhibitor (ID) proteins, factors that regulate DNA transcription, at different phases of PVH [35].…”