Biology subjects

Rahaman, S. O.

Publications and source records attributed to Rahaman, S. O..

5 recordsLinked to original sources

bioRxiv2024

TRPV4 calcium-permeable channel contributes to valve stiffening in aortic stenosis

Aortic valve stenosis (AVS) is a progressive disease marked by fibrosis, inflammation, calcification, and stiffening of the aortic valve leaflets, leading to disrupted blood flow and left ventricular pressure overload. AVS can result in heart failure and death within 2 to 5 years if left untreated, highlighting its high mortality rate. Understanding the molecular mechanisms of AVS is essential for developing noninvasive treatments. Emerging data suggest that extracellular and intracellular matrix stiffness influences gene expression, inflammation, and cell differentiation. Myofibroblast activation of valvular interstitial cells (VICs) along with excess extracellular matrix (ECM) accumulation and remodeling are primary drivers of AVS progression. Inflammation also plays a critical role, with macrophages accumulating in valve leaflets from AVS patients, promoting inflammation, activating VICs, and synthesizing and remodeling the ECM. Our lab and others have reported that macrophage and fibroblast activities, including migration, inflammatory gene expression, and myofibroblast activation, are sensitive to matrix stiffness, indicating that valve leaflet stiffening may regulate AVS progression via a cellular stiffness sensor. Our published work shows that mechanosensitive Ca2+-permeable transient receptor potential vanilloid 4 (TRPV4) channels regulate fibrosis in other organs and control macrophage and fibroblast activation, suggesting TRPV4 as the potential stiffness sensor in AVS. This implies that fibrosis and tissue stiffening may reinforce each other, creating a vicious cycle in AVS development, with VICs and macrophages playing central roles. Here, we identify the cellular stiffness sensor mediating the link between stiffness and AVS development using human aortic valve tissues, a murine model of aortic valve stenosis, and atomic force microscopy analysis.

pathology↗

bioRxiv2024

TRPV4 channel contributes to aortic root stiffening and atherosclerotic lesion development

Cardiovascular disease is the number one cause of death in the developed world and atherosclerosis, a chronic arterial disease, is the most dominant underlying pathology. Epidemiologic and experimental studies suggest that arterial stiffness is a risk factor for atherosclerosis. However, there has been surprisingly limited development in mechanistic understanding of the generation of arterial stiffness and little progress in understanding the mechanisms by which matrix stiffening drives the development of atherosclerosis. Various proinflammatory and fibrotic activities of macrophages and fibroblasts, such as migration, inflammatory gene expression, and myofibroblast activation, are influenced by matrix stiffness. This influence suggests that aorta stiffening may regulate atherosclerosis via a cellular stiffness sensor. Our research indicates that mechanosensitive transient receptor potential vanilloid 4 (TRPV4) channels control inflammation and fibrosis in other organs and regulate macrophage and fibroblast activation, implicating TRPV4 as a potential stiffness sensor in atherosclerosis. This suggests a cycle where inflammation, fibrosis, and tissue stiffening reinforce each other, with macrophages playing a key role. Here, we identify a cellular stiffness sensor linking matrix stiffness and atherosclerosis using human aortic tissues, a murine atherosclerosis model, and atomic force microscopy (AFM) analysis. This novel finding suggests that targeting TRPV4 could be a selective strategy to prevent or suppress atherogenesis.

pathology↗

bioRxiv2024

TRPV4-mediated Mechanotransduction Regulates the Differentiation of Valvular Interstitial Cells to Myofibroblasts: Implications for Aortic Stenosis

As aortic valve stenosis (AVS) progresses, the valve tissue also stiffens. This increase in tissue stiffness causes the valvular interstitial cells (VICs) to transform into myofibroblasts in response. VIC-to-myofibroblast differentiation is critically involved in the development of AVS. Herein, we investigated the role of mechanosensitive Ca2+-permeant transient receptor potential vanilloid 4 (Trpv4) channels in matrix stiffness- and transforming growth factor {beta}1 (TGF{beta}1)-induced VIC-myofibroblast activation. We confirmed Trpv4 functionality in primary mouse wild-type VICs compared to Trpv4 null VICs using live Ca2+ influx detection during application of its selective agonist and antagonist. Using physiologically relevant hydrogels of varying stiffness that respectively mimic healthy or diseased aortic valve tissue stiffness, we found that genetic ablation of Trpv4 blocked matrix stiffness- and TGF{beta}1-induced VIC-myofibroblast activation as determined by changes in morphology, alterations of expression of -smooth muscle actin, and modulations of F-actin generation. Our results showed that N-terminal residues 30-130 in Trpv4 were crucial for cellular force generation and VIC-myofibroblast activation, while deletion of residues 1-30 had no noticeable negative effect on these processes. Collectively, these data suggest a differential regulatory role for Trpv4 in stiffness/TGF{beta}1-induced VIC-myofibroblast activation. Our data further showed that Trpv4 regulates stiffness/TGF{beta}1-induced PI3K-AKT activity that is required for VIC-myofibroblast differentiation and cellular force generation, suggesting a mechanism by which Trpv4 activity regulates VIC-myofibroblast activation. Altogether, these data identify a novel role for Trpv4 mechanotransduction in regulating VIC-myofibroblast activation, implicating Trpv4 as a potential therapeutic target to slow and/or reverse AVS development.

cell biology↗

bioRxiv2024

Macrophage microRNA-146a is a central regulator of the foreign body response to biomaterial implants

Host recognition and immune-mediated foreign body response (FBR) to biomaterials can adversely affect the functionality of implanted materials. To identify key targets underlying the generation of FBR, here we perform analysis of microRNAs (miR) and mRNAs responses to implanted biomaterials. We found that (a) miR-146a levels inversely affect macrophage accumulation, foreign body giant cell (FBGC) formation, and fibrosis in a murine implant model; (b) macrophage-derived miR-146a is a crucial regulator of the FBR and FBGC formation, as confirmed by global and cell-specific knockout of miR-146a; (c) miR-146a modulates genes related to inflammation, fibrosis, and mechanosensing; (d) miR-146a modulates tissue stiffness near the implant during FBR; and (e) miR-146a is linked to F-actin production and cellular traction force induction, which are vital for FBGC formation. These novel findings suggest that targeting macrophage miR-146a could be a selective strategy to inhibit FBR, potentially improving the biocompatibility of biomaterials.

cell biology↗

bioRxiv2024

Mechanisms underlying TRPV4-mediated regulation of miR-146a expression

Persistent inflammation is a major contributor in the development of various inflammatory diseases like atherosclerosis. Our study investigates how transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, interacts with microRNA-146a (miR-146a), within the context of inflammation and atherosclerosis. Micro-RNAs play a critical role in controlling gene expression, and miR-146a is notable for its anti-inflammatory actions. TRPV4 is activated by diverse soluble and mechanical stimuli, and often associated with inflammatory responses in various diseases. Here, we find that TRPV4 negatively regulates miR-146a expression in macrophages, especially following stimulation by lipopolysaccharides or alterations in matrix stiffness. We show that in atherosclerosis, a condition characterized by matrix stiffening, TRPV4 decreases miR-146a expression in aortic tissue macrophages. We find that TRPV4s impact on miR-146a is independent of activation of NF{kappa}B, Stat1, P38, and AKT, but is rather mediated through a mechanism involving histone deacetylation instead of DNA methylation at the miR-146a promoter site. Furthermore, we show that N-terminal residues 1 to 130 in TRPV4 is essential in suppression of miR-146a expression in LPS-stimulated macrophages. Altogether, this study identifies a regulatory mechanism of miR-146a expression by TRPV4 which may open new potential therapeutic strategies for managing inflammatory diseases.

molecular biology↗