The study of changes in gene regulation of serotonin signaling pathway and circulating serotonin concentration in dogs with pulmonary hypertension due to degenerative mitral valve disease

Abstract

Pulmonary hypertension (PH) is an abnormal increase in pulmonary vascular pressure. In dogs, PH is commonly found secondary to degenerative mitral valve disease (DMVD), especially in small breed dogs. Serotonin, a biogenic amine playing an essential role in both physiology and abnormalities of several organs, is a vasoactive substance that has been one of the suspicious mediators for the development of PH. Both local and circulating effects of serotonin have been investigated to discover the involvement of serotonin and the pathogenesis of PH in both humans and animals. The present study aimed to investigate the local serotonin signaling in lung and pulmonary arteries (PA) and the source and differences of serotonin in platelets and plasma of dogs with PH secondary to DMVD compared to healthy dogs and DMVD dogs without PH. The lung and PA tissues of fourteen small-breed dogs were collected and divided into the control (n = 4), DMVD (n = 5) and DMVD+PH (n = 5) groups. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot were used to assess the expression of genes and proteins associating with the serotonin signaling pathway. To measure the platelet and plasma serotonin concentrations, whole blood was collected from sixty-two small-breed dogs divided into the control (n = 22), DMVD (n = 20) and DMVD+PH (n = 20) groups. The blood samples were prepared and measured by enzyme-linked immunosorbent assay (ELISA). The tendency of upregulated TPH-1, SERT, 5-HTR2A, ERK1/2 and pERK1/2 protein in PA tissues were found in DMVD dogs with and without PH, whereas the gene and protein expression in lung tissues was varied. The concentration of platelet serotonin of dogs with DMVD and high probability of PH (35.82 [2.69 - 126.35] ng/109 platelets) was decreased compared to DMVD dogs without PH (325.99 [96.84 - 407.66] ng/109 platelets) (p = 0.008). The concentration of plasma serotonin did not differ among all groups. These findings revealed that proteins related to the serotonin signaling pathway increased in dogs affected with DMVD with and without PH suggesting the local effect of serotonin in PA in dogs affected with DMVD with and without PH. In circulation, the degree of PH probability of dogs with PH secondary to DMVD is correlated with a decrease in platelet serotonin concentration. Roles of serotonin in PA and platelet serotonin should be investigated to elucidate the involvement of the local and systemic effect of the serotonin signaling pathway in dogs with naturally occurring PH due to DMVD.