Activation of ß3-AR by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue.

AIMS: ß3-AR (ß3-adrenergic receptor) is essential for cardiovascular homeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate ß3-AR activation-mediated PVAT function in AD/AA. METHODS AND RESULTS: Aortas from patients with thoracic aortic dissection (TAD) were collected to detect ß3-AR expression in PVAT. ApoE-/- and ß-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA, and subsequently received either placebo or mirabegron, a ß3-AR agonist. The results demonstrated an up-regulation of ß3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of ß3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor VEGF-C in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes (LNs) of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. CONCLUSIONS: Our findings illustrated the therapeutic potential of ß3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.

Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway.

Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory T cell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.

PDGF-D activation by macrophage-derived uPA promotes AngII-induced cardiac remodeling in obese mice.

Obesity-induced secretory disorder of adipose tissue-derived factors is important for cardiac damage. However, whether platelet-derived growth factor-D (PDGF-D), a newly identified adipokine, regulates cardiac remodeling in angiotensin II (AngII)-infused obese mice is unclear. Here, we found obesity induced PDGF-D expression in adipose tissue as well as more severe cardiac remodeling compared with control lean mice after AngII infusion. Adipocyte-specific PDGF-D knockout attenuated hypertensive cardiac remodeling in obese mice. Consistently, adipocyte-specific PDGF-D overexpression transgenic mice (PA-Tg) showed exacerbated cardiac remodeling after AngII infusion without high-fat diet treatment. Mechanistic studies indicated that AngII-stimulated macrophages produce urokinase plasminogen activator (uPA) that activates PDGF-D by splicing full-length PDGF-D into the active PDGF-DD. Moreover, bone marrow-specific uPA knockdown decreased active PDGF-DD levels in the heart and improved cardiac remodeling in HFD hypertensive mice. Together, our data provide for the first time a new interaction pattern between macrophage and adipocyte: that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice.

Downregulation of dynamin-related protein 1 contributes to impaired autophagic flux and angiogenic function in senescent endothelial cells.

OBJECTIVE: Recent studies have shown that altered mitochondrial dynamics impairs the function in senescent endothelial cells (ECs). However, the underlying molecular mechanism remains to be elucidated. Herein, we investigated the role and underlying mechanism of mitochondrial fission protein dynamin-related protein 1 (DRP1) in vascular aging. APPROACH AND RESULTS: We found that DRP1 expression is decreased in senescent ECs, accompanied with long interconnected mitochondria and impaired angiogenic function. In addition, there was marked increase of autophagosomes but not of autolysosomes (assessed as punctate dual fluorescent mCherry-GFP (green fluorescent protein) tandem-tagged light chain 3 expression) in senescent ECs, indicating impaired autophagic flux. DRP1 knockdown or pharmacological inhibition in young ECs resulted in elongated mitochondria, suppressed autophagic flux, premature senescence, and impaired angiogenic function. In contrast, adenoviral-mediated overexpression of DRP1 in senescent ECs restored autophagic flux and improved angiogenic function. EC senescence was associated with the increase of mitochondrial reactive oxygen species and antioxidant N-acetyl-cysteine restored autophagosome clearance and improved angiogenic function. Consistently, en face staining of old rat thoracic aorta revealed a decrease of DRP1 expression and increase of autophagosomes accumulation. Furthermore, in vivo knockdown of Drp1 in common carotid arteries significantly impaired the autophagosome clearance. Importantly, downregulation of Drp1 directly abrogated microvessels outgrowth from ex vivo aortic rings. CONCLUSIONS: These results suggest that loss of DRP1 during senescence exacerbates ECs dysfunction by increasing mitochondrial reactive oxygen species and subsequently inhibiting autophagic flux.

Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma.

Recent studies have shown that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are associated with the pathogenesis of aldosterone-producing adenoma. Clinical profile and biochemical characteristics of the mutations in Chinese patients with aldosterone-producing adenoma remain unclear. In this study, we performed DNA sequencing in 168 Chinese patients with aldosterone-producing adenoma and found 129 somatic mutations in KCNJ5, 4 in ATP1A1, 1 in ATP2B3, and 1 in CACNA1D. KCNJ5 mutations were more prevalent in female patients and were associated with larger adenomas, higher aldosterone excretion, and lower minimal serum K(+) concentration. More interestingly, we identified a novel somatic KCNJ5 mutation (c.445-446insGAA, p.T148-T149insR) that could enhance CYP11B2 mRNA upregulation and aldosterone release. This mutation could also cause membrane depolarization and intercellular Ca(2+) increase. In conclusion, somatic KCNJ5 mutations are conspicuously more popular than mutations of other genes in aldosterone-producing adenomas of Chinese patients. The T148-T149insR mutation in KCNJ5 may influence K(+) channel selectivity and autonomous aldosterone production.

[Retrospective study of complication of interspinous implants for degenerative lumbar disease].

OBJECTIVE: To summarize and analyze the complications of interspinous implants for degenerative lumbar disease. METHODS: From September 2007 to September 2011, 177 cases with degenerative lumbar diseases were treated with interspinous implants. There were 99 male patients and 78 female patients, the average age was 44.5 years (26 - 71 years). According to the application interspinous dynamic stabilization system type were divided into the Wallis group (136 cases) and Coflex group (41 cases). The clinical results were assessed by visual analog scale (VAS) of pain on lumbar and lower limbers, lumbar Japanese Orthopedic Association (JOA) score and Prolo functional score. The radiological results including segmental lodosis and segement movement degree were assessed by lumbar X ray and dynamic X ray. Summarize and analyze the complications both during operation and post operation. Quantitative datas were compared by paried-samples t test and complication rate was compared by χ(2) test. RESULTS: There were 168 cases had completed follow-up and the average time was 34.7 months (3 - 50 months). In the final follow-up, lumbar pain VAS, lower limber pain VAS, lumbar JOA score and Prolo functional score were better than pre-operation (t = 10.7, 7.9, 13.4 and 8.8, P < 0.01). Segment lodosis angles was 14° ± 4° which was less than pre-operation 19° ± 4° (t = 9.4, P < 0.01).Segment movement degree was larger in Coflex group (12.6° ± 3.1°) than in Wallis group (9.7° ± 2.7°) (t = 8.6, P < 0.05). Complication rate was 10.7% (18/168), which of Wallis group was 6.2% (8/130) and Coflex group was 26.3% (10/38) (χ(2) = 12.5, P < 0.01). In Wallis group, there were 3 cases with dura tear and cerebrospinal fluid leakage, 1 case with nerve root injury and foot drop, 2 cases with spacer breakage when implantation and change the implants and 2 cases with recurrence of lumbar disc herniation. In Coflex group, there was 1 case with dura tear and cerebrospinal fluid leakage, 2 cases with mild displacement post operation, 1 case with debridement for aseptic wound exudates, 1 case with implant removal for breakage 1 week post operation, 4 cases with recurrence of lumbar disc herniation and 1 case with lumbar disc herniation 6 months post operation of lumbar stenosis. CONCLUSIONS: The application of interspinous implants for degenerative lumbar diseases is effective and relative safe, but would suffer from the risk of complications.

[Prevention for venous thromboembolism prophylaxis after spinal surgery].

OBJECTIVE: To investigate the efficacy and safety of venous thrombus embolism (VTE) prophylaxis according to risk stratifications after spinal surgery. METHODS: From June 2008 to June 2009, we separated 298 spinal patients who had different VTE risk factors into low-, medium- and high-risk groups for 22 cases, 48 cases and 228 cases respectively. Physical prevention measures such as thigh-length thromboembolic deterrent stockings (TEDS) and pneumatic sequential compression device (PSCD) were used in low- and medium-risk groups. In high-risk groups, low molecular weight heparin(LMWH) was applied in addition to physical prevention measures. Lower limb vascular doppler ultrasonography was used to monitor thrombosis pre- and postoperatively. Simultaneously the occurrences of epidural or wound hematoma, mucosal bleeding, thrombocytopenia caused by low molecular heparin and nerve damage caused by extradural hemorrhage were monitored. RESULTS: Among the 298 cases of patients with spinal surgery, DVT occurred in 23 cases, the incidence of DVT was 7.7%. There were 0, 2 and 21 patients with positive findings of deep vein thrombosis on duplex ultrasonograph respectively in low-, medium- and high-risk groups. There was no case of PE. All DVT was thrombosis in calf which was distal to the knee. There was no clinical symptom of VTE. The DVT needed no therapy. The vein with thrombosis was recanalized 3 months after operation. No case caught epidural or wound hematoma, mucosal bleeding, thrombocytopenia caused by low molecular heparin or nerve damage caused by extradural hemorrhage. CONCLUSION: Individual VTE prophylaxis was taken according to risk stratifications. No VTE of clinical value or no complications from prophylaxis happened. So our prophylaxis is effective and safe. But more prospective, case-control studies are needed to assess the efficacy and safety of VTE prophylaxis.

[Retrospective study of combined application of interspinous process fixation system and rigid fixation system for degenerative lumbar diseases].

OBJECTIVE: To assess the efficacy and safety of combined application of interspinous process fixation system and rigid fixation system for degenerative lumbar diseases. METHODS: From September 2007 to September 2008, 16 cases with degenerative lumbar diseases were treated with combined application of interspinous process fixation system and rigid fixation system. The clinical results were assessed by VAS of pain of lumbar and lower limbs, lumbar JOA score and Prolo functional score. The radiological results including implant position (interspinous process, pedicle screws and plates), spinous process fracture, segmental range of motion (the non-fusion fixation segment, and the intermediate segments between fused and non-fused segments) which were assessed by lumbar static and dynamic X rays. RESULTS: All 16 cases obtained an average follow-up of 17.6 months. At final follow up, lumbar VAS, lower limbers VAS, lumbar JOA score and Prolo functional score were significant improved than those of pre-operation (lumbar VAS: 1.9 +/- 1.4 vs. 4.5 +/- 3.1; lower limbs VAS: 1.7 +/- 1.2 vs. 6.3 +/- 2.9; lumbar JOA score: 22.8 +/- 3.3 vs. 12.5 +/- 4.7; Prolo functional score: 8.3 +/- 1.2 vs. 4.0 +/- 2.3). Range of motion of the non-fusion fixation segment was (9.8 +/- 4.2) degrees and that of the intermediate segments between fused and non-fused segments was (13.2 +/- 3.5) degrees . CONCLUSIONS: Combined application of interspinous process fixation system and rigid fixation system for degenerative lumbar diseases provides a new idea to avoid the multi-segment fusion fixation and pertinent potential problems. Short-term clinical results are successful.