Insights into Serotonin Signaling Mechanisms Associated with Canine Degenerative Mitral Valve Disease

Abstract

Little is known about the molecular abnormalities associated with canine degenerative mitral valve disease (DMVD). The pathology of DMVD involves the differentiation and activation of the normally quiescent mitral valvular interstitial cell (VIC) into a more active myofibroblast phenotype, which mediates many of the histological and molecular changes in affected the valve tissue. In both humans and experimental animal models, increased serotonin (5-hydroxytryptamine, 5HT) signaling can induce VIC differentiation and myxomatous valve damage. In canine DMVD, numerous lines of evidence suggest that 5HT and related molecules such as transforming growth factor-b play a critical role in the pathogenesis of this disease. A variety of investigative techniques, including gene expression, immunohistochemistry, protein blotting, and cell culture, shed light on the potential role of 5HT in the differentiation of VIC, elaboration of myxomatous extracellular matrix components, and activation of mitogen-activated protein kinase pathways. These studies help support a hypothesis that 5HT and its related pathways serve as an important stimulus in canine DMVD. This review describes the pathological characteristics of canine DMVD, the organization and role of the 5HT pathway in valve tissue, involvement of 5HT in human and experimental models of valve disease, avenues of evidence that suggest a role for 5HT in naturally occurring DMVD, and finally, a overarching hypothesis describing a potential role for 5HT in canine DMVD.

Auscultatory, echocardiographic, biochemical, nutritional, and environmental characteristics of mitral valve disease in Norfolk terriers

“…15 5HT has been potentially shown to play a role in the pathophysiology of DMVD in dogs insofar as circulating concentrations are increased in animals with DMVD as well as in healthy Cavalier King Charles spaniels. 16,17 In the Norfolk terrier, median 5HT concentration was higher in dogs with DMVD although this did not reach statistical significance, and likely requires examination in a greater number of dogs to determine the clinical importance of such a finding. Thus, the role of 5HT in canine DMVD requires additional study.…”

Signaling pathways in mitral valve degeneration

“…Circulating serotonin has received recent attention as a possible initiating mechanism of canine DMVD. 17 It is well known that very high circulating serotonin levels associated with carcinoid syndrome (enterochromaffin cell neoplasia) induce valvulopathy in humans. 18 While the pathologic pattern of serotoninergic valvulopathy is not identical to degenerative valvulopathy, they do share the feature of being predominately myxomatous, i.e.…”

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

“…In humans, altered regulation of the serotonin pathway is thought to be associated with the development of pulmonary fibrosis since an increased expression of 5-HT receptors was found in IPF lungs (Fabre and Crestani, 2010;Konigshoff et al, 2010) and anti-serotonin therapy was shown to attenuate induced pulmonary fibrosis in mice (Konigshoff et al, 2010;Skurikhin et al, 2012). In dogs, 5-HT has essentially been studied in the pathogenesis of the DMVD, another fibrotic disease (Oyama and Levy, 2010;Ljungvall et al, 2013;Cremer et al, 2014;Mangklabruks and Surachetpong, 2014). Increased 5-HT blood concentrations were found in healthy KCS in comparison with healthy dogs from other breeds predisposed or not to DMVD (Arndt et al, 2009).…”