Association of Oral Anticoagulant Therapy with the Prevalence and Severity of Vascular Calcification among Patients with Atrial Fibrillation: A Cohort Study.

Many patients with atrial fibrillation (AF) requiring long-term use of oral anticoagulants (OACs) are at high risk for vascular calcification and anticoagulation therapy with warfarin exacerbate vascular calcification. However, the effect of nonvitamin K agonists on vascular calcification has not been clearly investigated. This study explored the effects of dabigatran etexilate, rivaroxaban, and warfarin on vascular calcification among 1527 patients with AF. Demographics, comorbidities, laboratory test data, medications, and the prevalence and severity of vascular calcification in different vascular beds were compared. After propensity score matching, the incidence of vascular calcification in the rivaroxaban and warfarin group was significantly higher than that in the nonanticoagulant group, while there was no difference between the dabigatran etexilate group and the nonanticoagulant group. Similarly, we found that the rivaroxaban group had more severe calcification in the overall vascular level (P < 0.001), thoracic aorta (P < 0.001), aortic arch (P = 0.001), and left common carotid artery (P = 0.005) than the nonanticoagulant group. In addition, in the left common carotid artery, there was more severe calcification in the rivaroxaban group than that in the dabigatran group (P = 0.005). Our results suggest that rivaroxaban can significantly increase both the incidence and severity of vascular calcification among patients with AF, while dabigatran etexilate has no such effect. Many patients with AF requiring long-term use of OACs are at high risk for vascular calcification. This is the first study to conduct a head-to-head comparison of the effects of dabigatran etexilate and rivaroxaban on vascular calcification. Rivaroxaban, rather than dabigatran etexilate, promotes vascular calcification in patients with AF, providing important implications to aid clinicians in their choice for OAC selection, especially those at high risk for vascular calcification.

CGRP attenuates pulmonary vascular remodeling by inhibiting the cGAS-STING-NFκB pathway in pulmonary arterial hypertension.

BACKGROUND: Hyperproliferation, inflammation, and mitochondrial abnormalities in pulmonary artery smooth muscle cells (PASMCs) underlie the pathological mechanisms of vascular remodeling in pulmonary arterial hypertension (PAH). Cytoplasmic mtDNA activates the cGAS-STING-NFκB pathway and secretes pro-inflammatory cytokines that may be involved in the pathogenesis of PAH. Calcitonin gene-related peptide (CGRP) acts as a vasodilator to regulate patterns of cellular energy metabolism and has vasodilatory and anti-inflammatory effects. METHODS: The role of the cGAS-STING-NFκB signaling pathway in PAH vascular remodeling and the regulation of CGRP in the cGAS-STING-NFκB signaling pathway were investigated by echocardiography, morphology, histology, enzyme immunoassay, and fluorometry. RESULTS: Monocrotaline (MCT) could promote right heart hypertrophy, pulmonary artery intima thickening, and inflammatory cell infiltration in rats. Cinnamaldehyde (CA)-induced CGRP release alleviates MCT-induced vascular remodeling in PAH. CGRP reduces PDGF-BB-induced proliferation, and migration, and downregulates smooth muscle cell phenotypic proteins. In vivo and in vitro experiments confirm that the mitochondria of PASMCs were damaged during PAH, and the superoxide and mtDNA produced by injured mitochondria activate the cGAS-STING-NFκB pathway to promote PAH process, while CGRP could play an anti-PAH role by protecting the mitochondria and inhibiting the cGAS-STING-NFκB pathway through PKA. CONCLUSION: This study identifies that CGRP attenuates cGAS-STING-NFκB axis-mediated vascular remodeling in PAH through PKA.

Betulinaldehyde inhibits vascular remodeling by regulating the microenvironment through the PLCγ1/Ca2+/MMP9 pathway.

BACKGROUND: Vascular remodeling plays a crucial role in the pathogenesis of several cardiovascular diseases (CVDs). Unfortunately, current drug therapies offer limited relief for vascular remodeling. Therefore, the development of innovative therapeutic strategies or drugs that target vascular remodeling is imperative. Betulinaldehyde (BA) is a triterpenoid with diverse biological activities, but its effects on vascular remodeling remain unclear. OBJECTIVE: This study aimed to investigate the role of BA in vascular remodeling and its mechanism of action, providing valuable information for future applications of BA in the treatment of CVDs. METHODS: Network pharmacology was used to predict the key targets of BA in vascular remodeling. The effect of BA on vascular remodeling was assessed in a rat model of balloon injury using hematoxylin and eosin staining, Masson staining, immunohistochemistry staining, and Western blotting. A phenotypic transformation model of vascular smooth muscle cells (VSMCs) was induced by platelet-derived growth factor-BB, and the functional impacts of BA on VSMCs were assessed via CCK-8, EdU, Wound healing, Transwell, and Western blotting. Finally, after manipulation of phospholipase C gamma1 (PLCγ1) expression, Western blotting and Ca2+ levels determination were performed to investigate the potential mechanism of action of BA. RESULTS: The most key target of BA in vascular remodeling, matrix metalloproteinase 9 (MMP9), was identified through network pharmacology screening. Vascular remodeling was alleviated by BA in vivo and its effects were associated with decreased MMP9 expression. In vitro studies indicated that BA inhibited VSMC proliferation, migration, phenotypic transformation, and downregulated MMP9 expression. Additionally, BA decreased PLCγ1 expression and Ca2+ levels in VSMCs. However, after pretreatment with a phospholipase C agonist, BA's effects on down-regulating the expression of PLCγ1 and Ca2+ levels were inhibited, while the expression of MMP9 increased compared to that in the BA treatment group. CONCLUSION: This study demonstrated the critical role of BA in vascular remodeling. These findings revealed a novel mechanism whereby BA mediates its protective effects through MMP9 regulation by inhibiting the PLCγ1/Ca2+/MMP9 signaling pathway. Overall, BA may potentially be developed into a novel medication for CVDs and may serve as a promising therapeutic strategy for improving recovery from CVDs by targeting MMP9.