α1AMP-activated protein kinase mediates vascular protective effects of exercise.

OBJECTIVE: We investigated whether AMP-activated protein kinase (AMPK) may be involved in the signaling processes leading to exercise-mediated vascular protection. METHODS AND RESULTS: The effects of voluntary exercise on AMPK activity, endothelial NO synthase expression and phosphorylation, vascular reactive oxygen species formation, and cell senescence were tested in α1AMPK knockout and corresponding wild-type mice. Exercise significantly improved endothelial function, and increased plasma nitrite production in wild-type mice, associated with an activation of aortic AMPK assessed by its phosphorylation at threonine 172. In addition, regular physical activity resulted in an upregulation of endothelial NO synthase protein, serine 1177 endothelial NO synthase phosphorylation, and an increase of circulating Tie-2(+)Sca-1(+)Flk-1(+) myeloid progenitor cells. All these changes were absent after α1AMPK deletion. In addition, exercise increased the expression of important regulators of the antioxidative defense including heme oxygenase-1 and peroxisome proliferator-activated receptor γ coactivator 1α, decreased aortic reactive oxygen species levels, and prevented endothelial cell senescence in an α1AMPK-dependent manner. CONCLUSIONS: Intact α1AMPK signaling is required for the signaling events leading to the manifestation of vascular protective effects during exercise. Pharmacological AMPK activation might be a novel approach in the near future to simulate the beneficial vascular effects of physical activity.

Comparison of long-term outcome in patients with calcified stenosis treated with intravascular lithotripsy or with modified balloon angioplasty: a propensity score-adjusted study.

Background: The aim of this two-center, all-comers registry was to compare the effectiveness and safety of intravascular lithotripsy (IVL) to that of modified balloon angioplasty (MB). MB angioplasty using a cutting or scoring balloon is commonly used in patients with calcified coronary arteries. IVL is a new technology for lesion preparation. This is the first study to compare MB with IVL. Methods: The cohort included all patients treated by MB angioplasty or IVL between 2019 and 2021. The primary endpoint was strategy success (<20% residual stenosis). The secondary endpoint was long-term safety outcomes [cardiac death, acute myocardial infarction (AMI), target lesion failure/revascularization (TVR)]. Quantitative coronary angiography (QCA) was performed in all patients. Primary and secondary endpoints were compared using inverse probability of treatment weighting (IPTW) for treatment effect estimation. Results: A total of n = 86 patients were treated by IVL and n = 92 patients by MB angioplasty. The primary endpoint was reached in 152 patients (85.4%). Patients in the IVL group had less residual stenosis (5.8% vs. 22.8%; p = 0.001) in QCA. Weighted multivariable regression analysis revealed that IVL had a significant positive effect on reaching the primary endpoint of strategy success [odds ratio (OR) 24.58; 95% confidence interval (95% CI) 7.40-101.86; p = 0.001]. In addition, severe calcification was shown to result in a lower probability of achieving the primary endpoint (OR 0.08; 95% CI 0.02-0.24; p = 0.001). During the follow-up period (450 days) there was no difference in cardiovascular mortality rate [IVL (n = 5) 2.8% vs. MB (n = 3) 1.7%; p = 0.129]. Patients with unstable angina at the time of the index procedure had the highest probability of cardiovascular death [hazard ratio (HR) 7.136; 95% CI 1.248-40.802; p = 0.027]. No differences were found in long-term rates of AMI (IVL 1.7% vs. MB 2.8%; p = 0.399; IVL HR 2.73; 95% CI 0.4-17.0; p = 0.281) or TVR (IVL 5.6% vs. MB 9%; p = 0.186; IVL HR 0.78; 95% CI 0.277-2.166; p = 0.626). Conclusion: IVL leads to a significantly better angiographic intervention outcome compared to MB angioplasty in our cohort. During long-term follow-up, no differences in cardiovascular mortality, rate of acute myocardial infarction, or target lesion failure/revascularization were observed.

Distinct CD11b+-monocyte subsets accelerate endothelial cell recovery after acute and chronic endothelial cell damage.

BACKGROUND: Endothelial cell recovery requires replenishment of primary cells from the endothelial lineage. However, recent evidence suggests that cells of the innate immune system enhance endothelial regeneration. METHODS AND RESULTS: Focusing on mature CD11b+-monocytes, we analyzed the fate and the effect of transfused CD11b+-monocytes after endothelial injury in vivo. CD11b-diphtheria-toxin-receptor-mice--a mouse model in which administration of diphtheria toxin selectively eliminates endogenous monocytes and macrophages--were treated with WT-derived CD11b+-monocytes from age-matched mice. CD11b+-monocytes improved endothelium-dependent vasoreactivity after 7 days while transfusion of WT-derived CD11b--cells had no beneficial effect on endothelial function. In ApoE-/--CD11b-DTR-mice with a hypercholesterolemia-induced chronic endothelial injury transfusion of WT-derived CD11b+-monocytes stimulated by interferon-γ (IFNγ) decreased endothelial function, whereas interleukin-4-stimulated (IL4) monocytes had no detectable effect on vascular function. Bioluminescent imaging revealed restriction of transfused CD11b+-monocytes to the endothelial injury site in CD11b-DTR-mice depleted of endogenous monocytes. In vitro co-culture experiments revealed significantly enhanced regeneration properties of human endothelial outgrowth cells (EOCs) when cultured with preconditioned-media (PCM) or monocytes of IL4-stimulated-subsets compared to the effects of IFNγ-stimulated monocytes. CONCLUSION: CD11b+-monocytes play an important role in endothelial cell recovery after endothelial injury by homing to the site of vascular injury, enhancing reendothelialization and improving endothelial function. In vitro experiments suggest that IL4-stimulated monocytes enhance EOC regeneration properties most likely by paracrine induction of proliferation and cellular promotion of differentiation. These results underline novel insights in the biology of endothelial regeneration and provide additional information for the treatment of vascular dysfunction.