Biology subjects

Rosenkranz, S.

Publications and source records attributed to Rosenkranz, S..

4 recordsLinked to original sources

bioRxiv2026

An Apoptotic Failsafe Program Involving PDGF-dependent PI 3-Kinase Activity Contributes to Plaque Composition in Atherosclerosis

Background: Growth and stability of atherosclerotic plaques are impacted by vascular smooth muscle cell (VSMC) apoptosis which is believed to be suppressed by growth factor dependent activation of phosphoinositide 3-kinase (PI3K). Here, we analyzed the effects of chronically elevated platelet-derived growth factor receptor {beta} (PDGFR{beta}) signaling on VSMC apoptosis and aortic plaque composition during atherogenesis. Methods: We assessed atherosclerosis in low-density lipoprotein receptor deficient mice, lacking low-density lipoprotein receptor-related protein 1 in VSMCs (LDLR-/-smLRP1-/- mice), in that smLRP1 deficiency resulted in PDGFRB overexpression. Apoptosis and downstream signaling was investigated in cultured aortic VSMCs. Results: Chronically elevated PDGFR{beta} signaling in LDLR-/-smLRP1-/- mice unexpectedly increased VSMC apoptosis in atherosclerotic plaques. In vitro, PDGF exerted transient anti-apoptotic effects on VSMCs, whereas long-term stimulation promoted cell death. Mutation of the PI3K binding site in the PDGFR{beta} (PDGFR{beta}-F2/F2) reduced VSMC apoptosis in plaques as well as in cultured VSMCs. Further analyses revealed that PI3K isoform p110 mediates VSMC survival, whereas p110{delta} and p110{beta} rather promote apoptosis. We identified a pro-apoptotic PDGFR{beta}-driven signaling pathway in VSMCs involving PI3K-dependent induction of c-Myc that in turn suppresses the expression of anti-apoptotic Bcl-2. PDGF-dependent downregulation of Bcl-2 increases the susceptibility of VSMCs to apoptotic agonists like H2O2 or Fas ligand. Consistently, Bcl-2 expression was elevated in plaques from PDGFR{beta}-F2/F2 mice. Conclusions: Our study expands the understanding of the role of growth factors in regulating apoptosis and argues against their role as pure survival factors. This has direct implications in atherogenesis, as chronically elevated PDGF does not mediate VSMC survival in atherosclerotic plaques, but rather promotes cell death in the VSMC-rich fibrous cap, thus promoting plaque instability and rupture.

biochemistry↗

bioRxiv2024

Targeting ADORA-PDE10 cAMP Microdomain: A Novel Therapeutic Approach for Pulmonary Hypertension

Despite substantial advancements in the treatment of pulmonary arterial hypertension (PAH), obstacles remain in achieving optimal outcomes. In this study, we focus on understanding the therapeutic effect of targeting the ADORA1/PDE10A-regulated cyclic AMP (cAMP) microenvironment in treating pulmonary hypertension. Screening of differentially expressed adenosine receptors in samples derived from healthy individuals and patients with idiopathic pulmonary arterial hypertension (IPAH) showed that ADORA1 expression was significantly upregulated under disease conditions. Functional studies revealed that, upon ADORA1 inhibition, donor hPASMCs showed anti-proliferative, pro-apoptotic features and increased intracellular cAMP levels. Surprisingly, the same effects were not replicated in IPAH PASMCs, suggesting the presence of another cAMP regulatory factor in close proximity to ADORA1 in IPAH PASMCs. To investigate this point, we performed protein-protein interaction studies in IPAH PASMCs and found that Phosphodiestrase 10A (PDE10A) co-localizes with ADORA1 under disease conditions. Moreover, we observed that ADORA1 and PDE10A form a regulatory complex in the A kinase anchoring protein 5 (AKAP5) microdomain. Silencing or dual inhibition of both ADORA1 and PDE10A in IPAH PASMCs induced anti-proliferative and pro-apoptotic effects with increased intracellular cAMP levels. To investigate the effects of the dual inhibitor in vivo, we administered it to both MCT and Sugen5416/hypoxia (SuHx) rat models of PAH, showing improved right ventricle function, reduced pulmonary vascular resistance and decreased lung vascular remodeling. In conclusion, we provide evidence that dual pharmacological targeting of ADORA1 and PDE10A has high therapeutic potential against PAH.

molecular biology↗

bioRxiv2022

PI 3-kinase isoform p110alpha controls smooth muscle cell functionality and protects against aortic aneurysm formation

BackgroundCatalytic class IA PI 3-kinase isoform p110 is a crucial regulator of cellular proliferation and survival in numerous cell types. While p110 is critically involved in pathogenic vascular remodeling, its physiological role for vascular integrity under stress conditions has not been studied. We report a protective function of smooth muscle p110 against abdominal aortic aneurysm (AAA) formation. Methods & ResultsIn mice lacking p110 in smooth muscle cells (sm-p110-/-), perfusion of the infrarenal aorta with porcine pancreatic elastase (PPE) yielded substantially enhanced AAA formation compared to wild type controls. This disease phenotype is partly attributable to a subtle preexisting vascular phenotype under basal conditions, as sm-p110-/- mice displayed a smaller media area, deranged aortic wall structure (detached smooth muscle cells, increased apoptotic cell death), and a diminished functional responsiveness of aortic rings to vasodilators. Furthermore, p110 is also implicated in regenerative processes during AAA development: Whereas wild type mice showed increased media hypertrophy, neointima formation and proliferation upon PPE intervention, these vascular remodeling processes were diminished in sm-p110-/- mice. Concomitantly, increased numbers of elastic fiber breaks and ECM degradation were detected in sm-p110-/- aorta. Mechanistically, we found that lack of p110 expression impaired smooth muscle cell proliferation, expression of contractile marker genes and production of elastin fibers. This phenotype largely depended on reduced phosphorylation and inactivation of FOXO1, as specific FOXO1 inhibition fully rescued proliferation of p110-/- smooth muscle cells, and knockdown of FOXO1 increased expression of calponin and elastin. ConclusionsSmooth muscle p110 protects against AAA disease by maintaining aortic wall homoeostasis and promoting SMC proliferation to compensate for cell loss during AAA development. Our findings have potential implications for current approaches aimed at p110 inhibition for cancer therapy and suggest new pharmacological strategies to activate p110 signaling in AAA disease.

cell biology↗

bioRxiv2018

Short-term aerobic training does not improve memory functioning in relapsing remitting multiple sclerosis - a randomized controlled trial

BackgroundOnly few aerobic exercise intervention trials specifically targeting cognitive functioning have been performed in MS.\n\nObjective and methodsThis randomized controlled trial aimed to determine the effects of aerobic exercise on cognition in relapsing-remitting MS. The primary outcome was verbal memory (Verbal learning and memory test, VLMT). Patients were randomized to an intervention group (IG) program or a waitlist control group (CG). Patients in the IG exercised according to an individually tailored training schedule (with 2-3 sessions per week for 12 weeks). The primary analysis was carried out using the intention-to-treat (ITT) sample with ANCOVA adjusting for baseline scores.\n\nResults77 RRMS patients were screened and 68 participants randomized (CG n=34; IG n=34). The sample comprised 68% females, had a mean age of 39 years, a mean disease duration of 6.3 years, and a mean EDSS of 1.8. No significant effects were detected in the ITT analysis for the primary endpoint VLMT or any other cognitive measures. Moreover, no significant treatment effects were observed for quality of life, fatigue, or depressive symptoms.\n\nConclusionThis study failed to demonstrate beneficial effects of aerobic exercise on cognition in RRMS.\n\nThe trial was prospectively registered at clinicaltrials.gov (NCT02005237).

clinical trials↗