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The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular fibrosis. Endoplasmic reticulum (ER) stress occurs after the dysfunction of ER and its structure. The three signals PERK/ATF-4, IRE-1α/XBP-1s and ATF6 are activated upon ER stress. Recent reports have suggested that the activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling contributes to cardiovascular fibrosis. However, whether TMAO mediates aortic valve fibrosis by activating PERK/ATF-4 and IRE-1α/XBP-1s signaling remains unclear. Human aortic valve interstitial cells (AVICs) were isolated from aortic valve leaflets. PERK IRE-1α, ATF-4, XBP-1s and CHOP expression, and production of collagen Ⅰ and TGF-β1 were analyzed following treatment with TMAO. The role of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in TMAO-induced fibrotic formation was determined using inhibitors and small interfering RNA. Diseased valves produced greater levels of ATF-4, XBP-1, collagen Ⅰ and TGF-β1. Interestingly, diseased cells exhibited augmented PERK/ATF-4 and IRE-1α/XBP-1s activation after TMAO stimulation. Inhibition and silencing of PERK/ATF-4 and IRE-1α/XBP-1s each resulted in enhanced suppression of TMAO-induced fibrogenic activity in diseased cells. Mice treated with dietary choline supplementation had substantially increased TMAO levels and aortic valve fibrosis, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. Moreover, a high-choline and high-fat diet remodeled the gut microbiota in mice. TMAO promoted aortic valve fibrosis through activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in vitro and in vivo. Modulation of diet, gut microbiota, TMAO, PERK/ATF-4 and IRE1-α/XBP-1s may be a promising approach to prevent aortic valve fibrosis. [Display omitted] • ATF-4 and XBP-1 are activated in human aortic valves. • PERK/ATF-4 and IRE-1α/XBP-1s signaling promotes TMAO-induced fibrotic formation in VICs. • Supplemental choline and fat diet remodels the gut microbiota and elevates circulating TMAO levels. • Elevated circulating TMAO increases aortic valve fibrosis in vivo. [ABSTRACT FROM AUTHOR]

Calcific aortic stenosis is a common disease, and some of its early causes are the activation and differentiation of resident fibroblasts to myofibroblasts in response to transforming growth factor β1 (TGF-β1). The aim of this study was to understand how TGF-β1 and its downstream effector, OB-cadherin [cadherin 11 (CDH11)], regulate porcine myofibroblast phenotypes. Based on whole-genome microarrays, 95 and 107 genes are up- and down-regulated at both the early (8 h) and the late (24 h) time points of TGF-β1 treatment. Gene functions related to cell adhesion, skeletal system development, and extracellular matrix are up-regulated by TGF-β1, whereas oxidation-reduction and steroid metabolic process are down-regulated. Notably, one of the cell adhesion molecules, CDH11, is up-regulated by ~2-fold through both the Smad2/3 and the ERK pathways elicited by TGF-β1. CDH11 mediates cell-cell contacts in both valvular fibroblasts and myofibroblasts. Knockdown of CDH11 by small interfering RNA increases the myofibroblast phenotype, including an ~2-fold increase in a-smooth muscle actin (α-SMA) expression and stress fiber formation. In contrast, increased binding of CDH11 through antibody treatment inhibits α-SMA expression. This study presents gene functional changes in response to TGF-β1 at the systems level and supports an inhibitory role of CDH11 in myofibroblast differentiation. [ABSTRACT FROM AUTHOR]

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Background: Auscultation of patients with mitral annular calcification on echocardiography revealed a particular constellation of findings.Objective: To test the hypothesis that a particular auscultatory constellation provides a high degree of certainty in diagnosing the combination of mitral annular calcification and aortic sclerosis so often found in the elderly.Methods: Two groups of patients were studied to evaluate the particular auscultatory constellation under consideration which consisted of: (1) a harsh ejection systolic murmur heard from the 2nd right interspace to the cardiac apex and usually loudest between the 3rd left interspace and the apex; (2) the murmur radiates from the apex towards the left axilla and radiates poorly or not at all from the 2nd right interspace to the neck, and (3) the 2nd heart sound at the cardiac base is normal in intensity, and no ejection clicks are present. Group 1 consisted of patients with mitral annular calcification on echocardiographic examination, and group 2 consisted of patients in whom the particular constellation of auscultatory findings was present and who were then referred for echocardiographic assessment.Results: The particular auscultatory constellation under investigation allowed the diagnosis of the presence of the combination of mitral annular calcification and aortic sclerosis with substantial accuracy.Conclusion: The findings in this exploratory study suggest that the pathologic combination of mitral annular calcification and aortic sclerosis can be diagnosed with a reasonably high degree of certainty in elderly patients, if the particular auscultatory configuration is identified. [ABSTRACT FROM AUTHOR]

Calcific aortic stenosis is a common disease, and some of its early causes are the activation and differentiation of resident fibroblasts to myofibroblasts in response to transforming growth factor β1 (TGF-β1). The aim of this study was to understand how TGF-β1 and its downstream effector, OB-cadherin [cadherin 11 (CDH11)], regulate porcine myofibroblast phenotypes. Based on whole-genome microarrays, 95 and 107 genes are up- and down-regulated at both the early (8 h) and the late (24 h) time points of TGF-β1 treatment. Gene functions related to cell adhesion, skeletal system development, and extracellular matrix are up-regulated by TGF-β1, whereas oxidation-reduction and steroid metabolic process are down-regulated. Notably, one of the cell adhesion molecules, CDH11, is up-regulated by ∼2-fold through both the Smad2/3 and the ERK pathways elicited by TGF-β1. CDH11 mediates cell-cell contacts in both valvular fibroblasts and myofibroblasts. Knockdown of CDH11 by small interfering RNA increases the myofibroblast phenotype, including an ∼2-fold increase in α-smooth muscle actin (α-SMA) expression and stress fiber formation. In contrast, increased binding of CDH11 through antibody treatment inhibits α-SMA expression. This study presents gene functional changes in response to TGF-β1 at the systems level and supports an inhibitory role of CDH11 in myofibroblast differentiation., (© FASEB.)