Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline‐deprived myocardium: the effects of carnitine

Abstract

Choline has been identified as an essential nutrient with crucial role in many vital biological functions. Recent studies have demonstrated that heart dysfunction can develop in the setting of choline deprivation even in the absence of underlying heart disease. Matrix metalloproteinases (MMPs) are responsible for extracellular matrix degradation, and the dysregulation of MMP-2 and MMP-9 has been involved in the pathogenesis of various cardiovascular disorders. The aim of the study was to investigate the role of MMPs and their inhibitors (TIMPs), in the pathogenesis of choline deficiency-induced cardiomyopathy, and the way they are affected by carnitine supplementation. Male Wistar Albino adult rats were divided into four groups and received standard or choline-deficient diet with or without L-carnitine in drinking water (0.15% w/v) for 1 month. Heart tissue immunohistochemistry for MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed. Choline deficiency was associated with suppressed immunohistochemical expression of MMP-2 and an increased expression of TIMP-2 compared to control, while it had no impact on TIMP-1. MMP-9 expression was decreased without, however, reaching statistical significance. Carnitine did not affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. The pattern of TIMP and MMP modulation observed in a choline deficiency setting appears to promote fibrosis. Carnitine, although shown to suppress fibrosis, does not seem to affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. Further studies will be required to identify the mechanism underlying the beneficial effects of carnitine.

The impact of dietary choline-deprivation on kidneys and heart of stz-induced diabetic rats

“…Moreover, choline deficiency induced dysregulation of MMPs/TIMPs in rat myocardial tissue, through significant decrease in MMP-2/TIMP-2 ratio which confirm the increases in extracellular matrix turnover state in rat myocardium induced by a dietary choline deficiency; the studied ratio of MMP-2/TIMP-2 reflecting the ECM dynamics that are indispensable during restructuring of tissue architecture confirmed that dietary deprivation of choline triggers collagen accumulation and deposition leading to cardiac interstitial fibrosis (Strilakou et al, 2016). MMPs are interfering with cell proliferation, differentiation, inflammation and triggering of angiogenesis via increase of VEGF expression in heart (Sang, 1998;Okazaki et al, 2014).…”

“…We have previously reported the early deleterious effect of Ch-deprivation on the adult healthy rat myocardium (Strilakou et al, 2013) (Strilakou et al, 2016). We herein provide novel findings that Chdeprivation aggravates the myocardial architecture and potential performance in STZ-induced diabetic adult rats.…”

“…Deficiency in choline is known to increase VEGF-A expression (Mehedint e t al., 2010;Kaji et al, 2011;Takeuchi et al, 2013). Previous reports have revealed that heart diastolic dysfunction and fibrosis were associated with an increase in MMPs activity and collagen turnover (Westermann et al, 2007a;Tozzi et al, 2007a); 4-weeks dietary choline deficiency induced functional impairment in heart associated with a focal inflammation and moderate myocardial fibrosis and a significant dysregulation in MMP-2/TIMP-2 ratio (Strilakou et al, 2013;Strilakou et al, 2016). Choline deficiency showed a pattern of MMP-2 immunohistochemical expression resembling to the one found in heart failure model (Tozzi et al, 2007a) as well as the IHC expression of MMP-2 and MMP-9 was similar to the expression in diabetic cardiomyopathy (van Linhout et al, 2008).…”

The association between RGS4 and choline in cardiac fibrosis

“…Choline plays an important physiological role in the development and function of the cardiovascular system. Choline deficiency is associated with significant cardiovascular incidence rate and even death rate [40,41]. According to Athina a. strilakou et al, choline deficiency has an adverse effect on cardiac function.…”

Nanoparticle-mediated arresten gene inhibits neointimal formation of vein grafts: an experimental research

“…Thus, cells in the media and adventitia can migrate; and in the end, the vessels can be restored. MMP are key enzymes in the degradation of the ECM (12) and the remodeling of the vascular wall. They are zinc dependent proteolytic enzymes that have a specific role in degrading the ECM (13,14).…”