The role of the disturbances in the intestinal barrier structure in relation to cardiovascular diseases pathogenesis and rebamipid potential in their correction

Cardiovascular diseases remain the leading cause of death worldwide, and today there is growing evidence of the important role of intestinal barrier disorders and microbiota imbalances in the development and progression of cardiovascular pathology. In this matter, changes in the structure of tight junctions between enterocytes of the intestinal mucous membrane have the leading importance, because normally they provide its barrier function, preventing the penetration into the systemic circulation both pathogens antigenic determinants and toxic products and biologically active substances. Impaired tight junctions and increased gastrointestinal mucous membrane permeability can be mediated by various mediators such as zonulin, an intestinal fatty acid-binding protein, as well as individual representatives of short-chain fatty acids. Increased intestinal permeability as well as its dysbiosis play a crucial role in the atherosclerosis progression, contributing to an increase in proinflammatory cytokines, chemoattractant molecules, and enhanced platelet reactivity. An important role in these processes is also played by trimethylamine oxide (TMAO), formed from the precursor synthesized by the intestinal microbiota. There is evidence that an elevated TMAO increases the risk of major adverse cardiovascular events, including death, myocardial infarction, and stroke. TMAO contribute to the atherosclerosis progression through various mechanisms - its inhibits the cholesterol reverse transport, which leads to its excretion impairment from macrophages and creates conditions for their transformation into foam cells and reduces the antiatherogenic effects of high density lipoproteins. The intestinal barrier and altered microbiome also contribute to the blood pressure dysregulation and predispose to arterial hypertension. The oxidized lipoproteins, which enter the bloodstream through the leaky intestinal mucosa, is also play important role in blood pressure increasing. A unique drug that can normalize the intestinal barrier function due to tight junctions’ repair is rebamipid. Distinctive features of this drug are its effectiveness throughout the whole gastrointestinal tract, as well as a wide range of pleiotropic effects, due to which rebamipid provides comprehensive mucous membrane protection at all three levels of its structural organization: at the preepithelial level, stimulating the mucins formation; at the epithelial level, restoring tight junctions and accelerating the cells regeneration; and subepithelial level, improving microcirculation in deep mucosa. Rebamipid has been used in clinical practice for a long time, due to this fact it has a wide body of evidence of high efficiency and safety, confirmed not only in experimental studies, but also in clinical trials. Additional, extremely important for cardiological patients, effects of rebamipide include directly anti-atherosclerotic and anti-inflammatory effects in the vascular bed, a beneficial effect on endothelial function and the activity in relation to the intestinal microbiome regulation. It was shown that rebamipid reduces the severity of intestinal mucosa damage induced by non-steroidal anti-inflammatory drugs, increases the lactobacilli level in the microbiome and reduces pathogenic bacteroids and clostridia. From the safety point of view, it is extremely important that even the triple rebamipide dose, studied in cardiologic patients, did not lead to the adverse drug reactions development. Such multifactorial pleiotropic rebamipide effects make it possible to consider it as a promising drug not only in the gastroenterologists’ practice, but also in the management of comorbid patients with cardiovascular diseases, including ischemic heart disease and arterial hypertension.

intestinal barrier, tight junctions, permeability, cardiovascular disease, atherosclerosis, arterial hypertension, rebamipid