Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease.

Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear.

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity.

Introduction: Sepsis is prevalent in the elderly population with increased incidence and mortality. Currently, the mechanism by which aging increases the susceptibility to sepsis and worsens outcome is unclear. We tested the that aging exacerbates cardiac dysfunction in sepsis through a Toll-like receptor 2 (TLR2)-dependent mechanism.

Recombinant IL-37 Exerts an Anti-inflammatory Effect on Human Aortic Valve Interstitial Cells through Extracellular and Intracellular Actions.

Calcific aortic valve disease (CAVD) is a chronic inflammatory disease with slow progression that involves soluble extracellular matrix (ECM) proteins. Previously, we found that recombinant interleukin (IL)-37 suppresses aortic valve interstitial cells (AVIC) inflammatory response through the interaction with IL-18 receptor α-chain (IL-18Rα) on the cell surface. Endogenous IL-37 can be retained in the cytoplasm or released into extracellular spaces.

Up-regulation of Myocardial Klotho Expression to Promote Cardiac Functional Recovery in Old Mice following Endotoxemia.

Objective: Endotoxemic cardiac dysfunction contributes to greater morbidity and mortality in elderly patients with sepsis. This study tested the hypothesis that Klotho insufficiency in aging heart exaggerates and prolongs myocardial inflammation to hinder cardiac function recovery following endotoxemia.

Methods: Endotoxin (0.

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3.

Calcific aortic valve disease (CAVD) is common in people over the age of 65. Progressive valvular calcification is a characteristic of CAVD and due to chronic inflammation in aortic valve interstitial cells (AVICs) resulting in CAVD progression. IL-38 is a naturally occurring anti-inflammatory cytokine; here, we report lower levels of endogenous IL-38 in AVICs isolated from patients' CAVD valves compared to AVICs from non-CAVD valves.

Elevated Expression of TLR2 in Aging Hearts Exacerbates Cardiac Inflammatory Response and Adverse Remodeling Following Ischemia and Reperfusion Injury.

Unlabelled: This study tested the hypothesis that Toll-like receptor 2 (TLR2) augments the inflammatory responses and adverse remodeling in aging hearts to exacerbate myocardial injury and cardiac dysfunction.

Methods: Old (20-22 months old) and adult (4-6 months old) mice of C57BL/6 wild-type and TLR2 knockout (KO) were subjected to coronary artery ligation (30 minutes) and reperfusion (3 or 14 days). Left ventricle function was assessed using a pressure-volume microcatheter.

Monocytes augment inflammatory responses in human aortic valve interstitial cells via β-integrin/ICAM-1-mediated signaling.

Objective: Inflammatory infiltration in aortic valves promotes calcific aortic valve disease (CAVD) progression. While soluble extracellular matrix (ECM) proteins induce inflammatory responses in aortic valve interstitial cells (AVICs), the impact of monocytes on AVIC inflammatory responses is unknown. We tested the hypothesis that monocytes enhance AVIC inflammatory responses to soluble ECM protein in this study.

Pro-inflammatory mediators released by activated monocytes promote aortic valve fibrocalcific activity.

Background: Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. Valvular fibrocalcification is a characteristic pathological change. In diseased valves, monocyte accumulation is evident, and aortic valve interstitial cells (AVICs) display greater fibrogenic and osteogenic activities.

Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip.

A three-dimensional microengineered human coronary artery-on-a-chip was developed for investigation of the mechanism by which low and oscillatory shear stress (OSS) induces pro-atherogenic changes. Single-cell RNA sequencing revealed that OSS induced distinct changes in endothelial cells (ECs) including pro-inflammatory endothelial-to-mesenchymal transition (EndMT). OSS promoted pro-inflammatory EndMT through the Notch1/p38 MAPK-NF-κB signaling axis.

Trimethylamine N-oxide induces osteogenic responses in human aortic valve interstitial cells in vitro and aggravates aortic valve lesions in mice.

Aims: Recent studies have shown that the choline-derived metabolite trimethylamine N-oxide (TMAO) is a biomarker that promotes cardiovascular disease through the induction of inflammation and stress. Inflammatory responses and stress are involved in the progression of calcified aortic valve disease (CAVD). Here, we examined whether TMAO induces the osteogenic differentiation of aortic valve interstitial cells (AVICs) through endoplasmic reticulum (ER) and mitochondrial stress pathways in vitro and in vivo.

Monocytes enhance the inflammatory response to TLR2 stimulation in aortic valve interstitial cells through paracrine up-regulation of TLR2 level.

Chronic valvular inflammation associated with monocyte infiltration promotes calcific aortic valve disease (CAVD) progression. Further, innate immunity in aortic valve interstitial cells (AVICs), mediated by Toll-like receptors (TLRs), up-regulates cellular inflammatory, fibrogenic and osteogenic activities. Currently, the pro-inflammatory communication between monocytes and AVICs and the underlying mechanism are unclear.

TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production.

Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening.

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells.

Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease. Soluble extracellular matrix (ECM) proteins can act as damage-associated molecular patterns and may induce valvular inflammation. Matrilin-2 is an ECM protein and has been found to elevate the pro-osteogenic activity in human aortic valve interstitial cells (AVICs).

MicroRNA-204 Deficiency in Human Aortic Valves Elevates Valvular Osteogenic Activity.

Aortic valve interstitial cells (AVICs) play a major role in valvular calcification associated with calcific aortic valve disease (CAVD). Although AVICs from diseased valves display a pro-osteogenic phenotype, the underlying mechanism causing this remains unclear. MicroRNA-204 (miR-204) is a negative regulator of osteoblast differentiation.

The intestinal microbiota associated with cardiac valve calcification differs from that of coronary artery disease.

Background And Aims: Although most risk factors for cardiac valve calcification (VC) are similar to those for coronary artery disease (CAD), they differ regarding lesions and clinical symptoms. Recently, increasing evidence suggests that intestinal bacteria play essential roles in cardiovascular disease (CVD). It is plausible that the gut microbiota is linked to the occurrence of different CVDs under similar risk factors.

Inhibition of secretory phospholipase A2 IIa attenuates prostaglandin E2-induced invasiveness in lung adenocarcinoma.

Secretory phospholipase A2 IIa (sPLA2 IIa) catalyzes the production of multiple inflammatory mediators that influence the development of lung and other cancers. The most potent of these carcinogenic mediators is prostaglandin E2 (PGE2). We hypothesize that sPLA2 IIa inhibition modulates the production of PGE2, and sPLA2 IIa inhibition exerts its antineoplastic effects via downregulation of PGE2 production.

Toll-Like Receptor-4 Is a Mediator of Proliferation in Esophageal Adenocarcinoma.

Background: Chronic inflammation from reflux disease has been implicated as part of the development of esophageal adenocarcinoma. Toll-like receptors (TLRs), a component of the innate immune system, have been implicated in mediating hyperplasia and metaplasia in response to inflammatory stimuli. Increased TLR4 in human esophageal cancer has been correlated with its carcinogenesis.

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells.

Objective: Extracellular matrix proteinases are implicated in the pathogenesis of calcific aortic valve disease. The ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin 2. We sought to determine the role of the ADAMTS5/matrilin 2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with calcific aortic valve disease.

Altered MicroRNA Expression Is Responsible for the Pro-Osteogenic Phenotype of Interstitial Cells in Calcified Human Aortic Valves.

Background: The transition of aortic valve interstitial cells (AVICs) to myofibroblastic and osteoblast-like phenotypes plays a critical role in calcific aortic valve disease progression. Several microRNAs (miRs) are implicated in stem cell differentiation into osteoblast. We hypothesized that an epigenetic mechanism regulates valvular pro-osteogenic activity.

An epigenetic regulatory loop controls pro-osteogenic activation by TGF-β1 or bone morphogenetic protein 2 in human aortic valve interstitial cells.

Calcific aortic valve disease (CAVD) is common in the elderly population, but pharmacological interventions for managing valvular calcification are unavailable. Transforming growth factor β1 (TGF-β1) and bone morphogenetic protein 2 (BMP-2) induce pro-osteogenic activation of human aortic valve interstitial cells (AVICs) that play an important role in valvular calcification. However, the molecular mechanism underlying pro-osteogenic activation in AVICs is incompletely understood.

Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis.

Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and overproduction of extracellular matrix (ECM) proteins.

Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9.

Unlabelled: Elevated level of blood phosphate (Pi) associated with chronic kidney disease (CKD) is a risk factor of aortic valve calcification. Aortic valve interstitial cells (AVICs) display osteogenic responses to high Pi although the underlying mechanism is incompletely understood. Sox9 is a pro-chondrogenic factor and may play a role in ectopic tissue calcification.

Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice.

Myocardial inflammatory responses to endotoxemia are enhanced in old mice, which results in worse cardiac dysfunction. Anti-inflammatory cytokine interleukin (IL)-37 has a broad effect on innate immunoresponses. We hypothesized that IL-37 suppresses myocardial inflammatory responses to protect cardiac function during endotoxemia in old mice.