CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation

Particulate ligands including cholesterol crystals and amyloid fibrils induce NLRP3-dependent production of interleukin-1β (IL-1β) in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands including oxidized-LDL, amyloid-β and amylin peptides accumulate in these diseases. Here we identify a CD36-mediated endocytic pathway that coordinates the intracellular conversion of these soluble ligands to crystals or fibrils, resulting in lysosomal disruption and NLRP3-inflammasome activation. Consequently, macrophages lacking CD36 failed to elicit IL-1β production in response to these ligands and targeting CD36 in atherosclerotic mice reduced serum IL-1β and plaque cholesterol crystal accumulation. Collectively, these findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation

Shear Stress Regulates Angiotensin Type 1 Receptor Expression in Endothelial Cells

Rationale: Shear stress (SS) has an established role in atherosclerotic plaque localization, but how it exerts its protective effect is not fully understood. Objective: To test the hypothesis that SS may downregulate angiotensin type 1 receptors (AT(1)Rs). Angiotensin II has been shown to be proinflammatory and to promote atherosclerosis. Methods and Results: Using immunohistochemistry, we found a pronounced expression of AT(1)R in the inner, atheroprone regions of the aortic arch of C57BL/6 and endothelial NO synthase-deficient (eNOS(-/-)) mice but not eNOS-overexpressing mice. In human umbilical vein endothelial cells (HUVECs), laminar SS (15 dyn/cm(2)) induced a biphasic decrease in AT(1)R protein expression characterized by a first reduction at 1 hour (31+/-4% of static control, P<0.01), partial recovery at 3 hours (65+/-9%), and a second more prolonged decline at 6, 12, and 24 hours (48+/-9%, 36+/-9%, 33+/-5%, respectively, P<0.05). One and 24 hours of SS significantly reduced fluorescent angiotensin binding compared to static HUVECs. Shear-induced downregulation of AT(1)R was abolished by treatment with protein kinase A and G inhibitors or N-G-nitro-L-arginine methyl ester (L-NAME). Fittingly, stimulating static HUVECs with an NO donor decreased AT(1)R protein levels. RT-PCR revealed a significant (P<0.05) decrease of AT(1)R mRNA in HUVECs exposed to SS during 3 (6+/-2% of static control), 6 (4+/-1%), 12 (4+/-1%), and 24 hours (15+/-4%), suggesting a transcriptional downregulation of AT(1)R at length. Finally, angiotensin-induced vascular cell adhesion molecule was abated in HUVECs exposed to SS and in the outer aortic arch of mice. Conclusions: Our results demonstrate that SS may convey some of its atheroprotective effects through downregulation of AT(1)R in endothelial cells. (Circ Res. 2009; 105: 869-875.

Hypoxia Induces Netrin-1 and Unc5b in Atherosclerotic Plaques Mechanism for Macrophage Retention and Survival

Nephrolog

Neuroimmune Guidance Cue Semaphorin 3E Is Expressed in Atherosclerotic Plaques and Regulates Macrophage Retention

Nephrolog

Beta-Blocker Use After Thoracic Endovascular Aortic Repair in Patients With Type B Aortic Dissection Is Associated With Improved Early Aortic Remodeling

OBJECTIVE: Beta-blockers (BBs) are first-line anti-impulse therapy for patients presenting with acute type B aortic dissection (TBAD). However, little is understood about their effects after aortic repair. The aim of the present study was to evaluate the role of postoperative BB use on the outcomes of thoracic endovascular aortic repair (TEVAR) in TBAD. METHODS: The Vascular Quality Initiative database was queried for all patients who had undergone TEVAR for TBAD from 2012 to 2020. Aortic-related reintervention, all-cause mortality, and the effects of TEVAR on false lumen thrombosis of the treated aortic segment were assessed and compared between patients treated with and without BBs postoperatively. Cox proportional hazards models were used to estimate the effect of BB therapy on the outcomes. RESULTS: A total of 1114 patients who had undergone TEVAR for TBAD with a mean follow-up of 18 ± 12 months were identified. The mean age was 61.1 ± 11.9 years, and 791 (71%) were men. Of the 1114 patients, 935 (84%) continued BB therapy at discharge and follow-up. The patients taking BBs were more likely to have had an entry tear originating in zones 1 to 2 (22% vs 13%; P = .022). The prevalence of acute, elective, and symptomatic aortic dissection, prevalence of concurrent aneurysms, number of endografts used, distribution of proximal and distal zones of dissection, and operative times were comparable between the two cohorts. At 18 months, significantly more complete false lumen thrombosis (58% vs 47%; log-rank P = .018) was observed for patients taking BBs, and the rates of aortic-related reinterventions (13% vs 9%; log-rank P = .396) and mortality (0.2% vs 0.7%; log-rank P = .401) were similar for patients taking and not taking BBs, respectively. Even after adjusting for clinical and anatomic factors, postoperative BB use was associated with increased complete false lumen thrombosis (hazard ratio, 1.56; 95% confidence interval, 1.10-2.21; P = .012) but did not affect mortality or aortic-related reintervention. A secondary analysis of BB use for those with acute vs chronic TBAD showed a higher rate of complete false lumen thrombosis for patients with chronic TBAD and taking BBs (59% vs 38%; log-rank P = .038). In contrast, no difference was found in the rate of complete false lumen thrombosis for those with acute TBAD between the two cohorts (58% vs 51%; log-rank P = .158). When analyzed separately, postoperative angiotensin-converting enzyme inhibitor use did not affect the rates of complete false lumen thrombosis, mortality, and aortic-related reintervention. CONCLUSIONS: BB use was associated with promotion of complete false lumen thrombosis for patients who had undergone TEVAR for TBAD. In addition to its role in the acute setting, anti-impulse control with BBs appears to confer favorable aortic remodeling and might improve patient outcomes after TEVAR, especially for those with chronic TBAD

Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice

Objectives: Obesity and obesity-associated inflammation is central to a variety of end-organ sequelae including atherosclerosis, a leading cause of death worldwide. Although mouse models have provided important insights into the immunopathogenesis of various diseases, modeling atherosclerosis in mice has proven difficult. Specifically, wild-type (WT) mice are resistant to developing atherosclerosis, while commonly used genetically modified mouse models of atherosclerosis are poor mimics of human disease. The lack of a physiologically relevant experimental model of atherosclerosis has hindered the understanding of mechanisms regulating disease development and progression as well as the development of translational therapies. Recent evidence suggests that housing mice within their thermoneutral zone profoundly alters murine physiology, including both metabolic and immune processes. We hypothesized that thermoneutral housing would allow for augmentation of atherosclerosis induction and progression in mice. Methods: ApoE−/− and WT mice were housed at either standard (TS) or thermoneutral (TN) temperatures and fed either a chow or obesogenic “Western” diet. Analysis included quantification of (i) obesity and obesity-associated downstream sequelae, (ii) the development and progression of atherosclerosis, and (iii) inflammatory gene expression pathways related to atherosclerosis. Results: Housing mice at TN, in combination with an obesogenic “Western” diet, profoundly augmented obesity development, exacerbated atherosclerosis in ApoE−/− mice, and initiated atherosclerosis development in WT mice. This increased disease burden was associated with altered lipid profiles, including cholesterol levels and fractions, and increased aortic plaque size. In addition to the mild induction of atherosclerosis, we similarly observed increased levels of aortic and white adipose tissue inflammation and increased circulating immune cell expression of pathways related to adverse cardiovascular outcome. Conclusions: In sum, our novel data in WT C57Bl/6 mice suggest that modulation of a single environmental variable, temperature, dramatically alters mouse physiology, metabolism, and inflammation, allowing for an improved mouse model of atherosclerosis. Thus, thermoneutral housing of mice shows promise in yielding a better understanding of the cellular and molecular pathways underlying the pathogenesis of diverse diseases. Keywords: Atherosclerosis, Thermoneutrality, Inflammatio

Endothelial Expression of Guidance Cues in Vessel Wall Homeostasis Dysregulation Under Proatherosclerotic Conditions

Nephrolog

Endothelial expression of guidance cues in vessel wall homeostasis: dysregulation under proatherosclerotic conditions

Background— Local modulation of vascular mammalian target of rapamycin (mTOR) signaling reduces smooth muscle cell (SMC) proliferation after endovascular interventions but may be associated with endothelial cell (EC) toxicity. The trilaminate vascular architecture juxtaposes ECs and SMCs to enable complex paracrine coregulation but shields SMCs from flow. We hypothesized that flow differentially affects mTOR signaling in ECs and SMCs and that SMCs regulate mTOR in ECs. Methods and Results— SMCs and/or ECs were exposed to coronary artery flow in a perfusion bioreactor. We demonstrated by flow cytometry, immunofluorescence, and immunoblotting that EC expression of phospho-S6 ribosomal protein (p-S6RP), a downstream target of mTOR, was doubled by flow. Conversely, S6RP in SMCs was growth factor but not flow responsive, and SMCs eliminated the flow sensitivity of ECs. Temsirolimus, a sirolimus analog, eliminated the effect of growth factor on SMCs and of flow on ECs, reducing p-S6RP below basal levels and inhibiting endothelial recovery. EC p-S6RP expression in stented porcine arteries confirmed our in vitro findings: Phosphorylation was greatest in ECs farthest from intact SMCs in metal stented arteries and altogether absent after sirolimus stent elution. Conclusions— The mTOR pathway is activated in ECs in response to luminal flow. SMCs inhibit this flow-induced stimulation of endothelial mTOR pathway. Thus, we now define a novel external stimulus regulating phosphorylation of S6RP and another level of EC-SMC crosstalk. These interactions may explain the impact of local antiproliferative delivery that targets SMC proliferation and suggest that future stents integrate design influences on flow and drug effects on their molecular targets