Biology subjects

Zimmermann, W.-H.

Publications and source records attributed to Zimmermann, W.-H..

3 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↗

bioRxiv2023

Bioengineering of a human innervated cardiac muscle model

Cardiac autonomic neurons control cardiac contractility. Dysregulation of the autonomic nervous system can lead to sympathetic overdrive resulting in heart failure and an increased incidence of fatal arrhythmias. Here, we introduce innervated engineered human myocardium (iEHM), a novel model of neuro-cardiac junctions, constructed by fusion of a bioengineered neural organoid (BENO) patterned to autonomic nervous system and engineered human myocardium (EHM). Projections of sympathetic neurons into engineered human myocardium formed presynaptic terminals in close proximity to cardiomyocytes and an extensive vascular network co-developing in the tissues. Contractile responses to optogenetic stimulation of the accordingly engineered neuronal component demonstrated functionality of neuro-cardiac junctions in iEHM. This model will serve as a human surrogate system to delineate neuron and cardiac cell contribution to brain and heart diseases and is an important step towards engineering a human brain to heart axis in a dish.

bioengineering↗

bioRxiv2023

LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome

Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. However, the underling disease mechanisms of LZTR1 missense variants driving the cardiac pathology are poorly understood. Hence, therapeutic options for Noonan syndrome patients are limited. In this study, we investigated the mechanistic consequences of a novel homozygous causative variant LZTR1L580Pby using patient-specific and CRISPR/Cas9-corrected iPSC-cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction of protein complexes uncovered a unique LZTR1L580P-specific disease mechanism provoking the cardiac hypertrophy. The homozygous variant was predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymer chains. The altered polymerization resulted in dysfunction of the LZTR1-cullin 3 ubiquitin ligase complexes and subsequently, in accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data showed that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via the autophagosome, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent proteasomal pathways. Importantly, uni-or biallelic genetic correction of the LZTR1L580P missense variant rescued the molecular and cellular disease-associated phenotype, providing proof-of-concept for CRISPR-based gene therapies.

cell biology↗