Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice.

Angiogenesis is a critical pathophysiological process involved in organ growth and various diseases. Transcription factors Sp1/Sp3 are necessary for fetal development and tumor growth. Sp1/Sp3 proteins were downregulated in the capillaries of the gastrocnemius in patients with critical limb ischemia samples. Endothelial-specific Sp1/Sp3 knockout reduces angiogenesis in retinal, pathological, and tumor models and induced activation of the Notch1 pathway. Further, the inactivation of VEGFR2 signaling by Notch1 contributes to the delayed angiogenesis phenotype. Mechanistically, endothelial Sp1 binds to the promoter of Notch1 and inhibits its transcription, which is enhanced by Sp3. The proangiogenic effect of ACEI is abolished in Sp1/Sp3-deletion male mice. We identify USP7 as an ACEI-activated deubiquitinating enzyme that translocated into the nucleus binding to Sp1/Sp3, which are deacetylated by HDAC1. Our findings demonstrate a central role for endothelial USP7-Sp1/Sp3-Notch1 signaling in pathophysiological angiogenesis in response to ACEI treatment.

Deletion of Smooth Muscle Lethal Giant Larvae 1 Promotes Neointimal Hyperplasia in Mice.

Vascular smooth muscle cell (VSMC) proliferation and migration contribute to neointimal hyperplasia after injury, which causes vascular remodeling related to arteriosclerosis, hypertension, and restenosis. Lethal giant larvae 1 (LGL1) is a highly conserved protein and plays an important role in cell polarity and tumor suppression. However, whether LGL1 affects neointimal hyperplasia is still unknown. In this study, we used smooth muscle-specific LGL1 knockout (LGL1SMKO) mice generated by cross-breeding LGL1flox/flox mice with α-SMA-Cre mice. LGL1 expression was significantly decreased during both carotid artery ligation in vivo and PDGF-BB stimulation in vitro. LGL1 overexpression inhibited the proliferation and migration of VSMCs. Mechanistically, LGL1 could bind with signal transducer and activator of transcription 3 (STAT3) and promote its degradation via the proteasomal pathway. In the carotid artery ligation animal model, smooth muscle-specific deletion of LGL1 accelerated neointimal hyperplasia, which was attenuated by the STAT3 inhibitor SH-4-54. In conclusion, LGL1 may inhibit neointimal hyperplasia by repressing VSMC proliferation and migration via promoting STAT3 proteasomal degradation.

Endothelial-to-Mesenchymal Transition in Calcific Aortic Valve Disease.

Calcific aortic valve disease (CAVD) represents a significant threat to cardiovascular health worldwide, and the incidence of this sclerocalcific valve disease has rapidly increased along with a rise in life expectancy. Compelling evidence has suggested that CAVD is an actively and finely regulated pathophysiological process even though it has been referred to as "degenerative" for decades. A striking similarity has been noted in the etiopathogenesis between CAVD and atherosclerosis, a classical proliferative sclerotic vascular disease.1 Nevertheless, pharmaceutical trials that attempted to target inflammation and dyslipidemia have produced disappointing results in CAVD. While senescence is a well-documented risk factor, the sophisticated regulatory networks have not been adequately explored underlying the aberrant calcification and osteogenesis in CAVD. Valvular endothelial cells (VECs), a type of resident effector cells in aortic leaflets, are crucial in maintaining valvular integrity and homeostasis, and dysfunctional VECs are a major contributor to disease initiation and progression. Accumulating evidence suggests that VECs undergo a phenotypic and functional transition to mesenchymal or fibroblast-like cells in CAVD, a process known as the endothelial-to-mesenchymal transition (EndMT) process. The relevance of this transition in CAVD has recently drawn great interest due to its importance in both valve genesis at an embryonic stage and CAVD development at an adult stage. Hence EndMT might be a valuable diagnostic and therapeutic target for disease prevention and treatment. This mini-review summarized the relevant literature that delineates the EndMT process and the underlying regulatory networks involved in CAVD.

Transcatheter aortic valve implantation in the patients with chronic liver disease: A mini-review and meta-analysis.

BACKGROUND: Chronic liver disease is traditionally conceived as a risk factor for cardiovascular surgery. Transcatheter aortic valve implantation (TAVI) has recently burgeoned to precede surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis at intermediate to high surgical risk. The evidence regarding TAVI in the patients with chronic liver disease is currently scarce. METHODS: This article aims to assess the application of TAVI technique in the patients with chronic liver disease. RESULTS: TAVI in the patients with chronic liver disease produced acceptable postoperative results. The post-TAVI outcomes were comparable between the patients with or without chronic liver disease, except for a lower rate of pacemaker implantation in the patients with chronic liver disease (OR, 0.49[0.27-0.87], P = .02). In the patients with chronic liver disease, compared to SAVR, TAVI led to a decrease in the in-hospital mortality (OR, 0.43[0.22-0.86], P = .02) and need for transfusion (OR, 0.39[0.25-0.62], P < .0001). The rest outcomes were similar between the 2 groups. CONCLUSIONS: This systematic review and meta-analysis supported that TAVI is a reliable therapeutic option for treating severe aortic stenosis in the patients with chronic liver disease. Future large-scale randomized controlled trials investigating the mid-term and long-term prognosis are needed to further verify these results.