pectins and Aortic-Valve-Stenosis

Modified citrus pectin (MCP) has a low-molecular-weight degree of esterification to allow absorption from the small intestinal epithelium into the circulation. MCP produces pleiotropic effects, including but not limited to its antagonism of galectin-3, which have shown benefit in preclinical and clinical models. Regarding cancer, MCP modulates several rate-limiting steps of the metastatic cascade. MCP can also affect cancer cell resistance to chemotherapy. Regarding fibrotic diseases, MCP modulates many of the steps involved in the pathogenesis of aortic stenosis. MCP also reduces fibrosis to the kidney, liver, and adipose tissue. Other benefits of MCP include detoxification and improved immune function. This review summarizes the pleiotropic effects of MCP.

Topics: Adipose Tissue; Aortic Valve Stenosis; Blood Proteins; Citrus; Fibrosis; Galectin 3; Galectins; Humans; Kidney Diseases; Liver Cirrhosis; Neoplasms; Pectins; Phytotherapy

Galectin-3 (Gal-3) is involved in cardiovascular fibrosis and aortic valve (AV) calcification. We hypothesized that Gal-3 pharmacological inhibition with modified citrus pectin (MCP) could reduce aortic and AV remodeling in normotensive rats with pressure overload (PO). Six weeks after aortic constriction, vascular Gal-3 expression was up-regulated in male Wistar rats. Gal-3 overexpression was accompanied by an increase in the aortic media layer thickness, enhanced total collagen, and augmented expression of fibrotic mediators. Further, vascular inflammatory markers as well as inflammatory cells content were greater in aorta from PO rats. MCP treatment (100 mg/kg/day) prevented the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of PO rats. Gal-3 levels were higher in AVs from PO rats. This paralleled enhanced AV fibrosis, inflammation, as well as greater expression of calcification markers. MCP treatment prevented the increase in Gal-3 as well as fibrosis, inflammation, and calcification in AVs. Overall, Gal-3 is overexpressed in aorta and AVs from PO rats. Gal-3 pharmacological inhibition blocks aortic and AV remodeling in experimental PO. Gal-3 could be a new therapeutic approach to delay the progression and the development of aortic remodeling and AV calcification in PO.

Topics: Animals; Aorta; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Disease Models, Animal; Galectin 3; Gene Expression Regulation; Male; Pectins; Rats; Rats, Wistar

Aortic stenosis (AS) is a chronic inflammatory disease, and calcification plays an important role in the progression of the disease. Galectin-3 (Gal-3) is a proinflammatory molecule involved in vascular osteogenesis in atherosclerosis. Therefore, we hypothesized that Gal-3 could mediate valve calcification in AS.. Blood samples and aortic valves (AVs) from 77 patients undergoing AV replacement were analyzed. As controls, noncalcified human AVs were obtained at autopsy (n=11). Gal-3 was spontaneously expressed in valvular interstitial cells (VICs) from AVs and increased in AS as compared to control AVs. Positive correlations were found between circulating and valvular Gal-3 levels. Valvular Gal-3 colocalized with the VICs markers, alpha-smooth muscle actin and vimentin, and with the osteogenic markers, osteopontin, bone morphogenetic protein 2, runt-related transcription factor 2, and SRY (sex-determining region Y)-box 9. Gal-3 also colocalized with the inflammatory markers cd68, cd80 and tumor necrosis factor alpha. In vitro, in VICs isolated from AVs, Gal-3 induced expression of inflammatory, fibrotic, and osteogenic markers through the extracellular signal-regulated kinase 1 and 2 pathway. Gal-3 expression was blocked in VICs undergoing osteoblastic differentiation using its pharmacological inhibitor, modified citrus pectin, or the clustered regularly interspaced short palindromic repeats/Cas9 knockout system. Gal-3 blockade and knockdown decreased the expression of inflammatory, fibrotic, and osteogenic markers in differentiated VICs.. Gal-3, which is overexpressed in AVs from AS patients, appears to play a central role in calcification in AS. Gal-3 could be a new therapeutic approach to delay the progression of AV calcification in AS.

Topics: Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aortic Valve; Aortic Valve Stenosis; B7-1 Antigen; Blood Proteins; Blotting, Western; Bone Morphogenetic Protein 2; Calcinosis; Case-Control Studies; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; CRISPR-Cas Systems; Female; Galectin 3; Galectins; Gene Knockdown Techniques; Heart Valve Prosthesis Implantation; Humans; In Vitro Techniques; Male; Osteoblasts; Osteopontin; Pectins; Prospective Studies; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; SOX9 Transcription Factor; Tumor Necrosis Factor-alpha

Galectin-3 (Gal-3), a β-galactoside-binding lectin, is increased in kidney injury and its pharmacological blockade reduces renal damage in acute kidney injury, hyperaldosteronism or hypertensive nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in early renal damage associated with obesity and aortic stenosis (AS).. Gal-3 was upregulated in kidneys from high fat diet (HFD) rats and in animals with partial occlusion of ascending aorta (AS). Urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL) and urinary albumin were enhanced in HFD and AS rats. In kidney from obese rats, fibrotic markers (collagen, TFG-β), epithelial-mesenchymal transition molecules (α-smooth muscle actin, E-cadherin), inflammatory mediator (osteopontin) and kidney injury marker (kidney injury molecule-1) were modified. In kidney from AS rats, fibrotic markers (collagen, CTGF), epithelial-mesenchymal transition molecules (fibronectin, α-smooth muscle actin, β-catenin, E-cadherin) and kidney injury markers (NGAL, kidney injury molecule-1) were altered. Histologic observations of obese and AS rat kidneys revealed tubulointerstitial fibrosis. The pharmacological inhibition of Gal-3 with MCP normalized renal Gal-3 levels as well as functional, histological and molecular alterations in obese and AS rats.. In experimental models of mild kidney damage, the increase in renal Gal-3 expression paralleled with renal fibrosis, inflammation and damage, while these alterations were prevented by Gal-3 blockade. These data suggest that Gal-3 could be a new player in renal molecular, histological and functional alterations at early stages of kidney damage.

Topics: Acute Kidney Injury; Animals; Aortic Valve Stenosis; Diet, High-Fat; Disease Models, Animal; Fibrosis; Galectin 3; Kidney; Male; Obesity; Pectins; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction