Biology subjects

Dewenter, M.

Publications and source records attributed to Dewenter, M..

7 recordsLinked to original sources

bioRxiv2026

Selective class IIa HDAC inhibition reverses diastolic dysfunction in cardiometabolic HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent cardiometabolic syndrome with yet no effective therapies. Here, we report that selectively class IIa histone deacetylases (HDACs) but no other classes of HDACs are enzymatically activated in hearts from HFpEF patients and cardiometabolic HFpEF animal models. Cell type-specific and enzymatic activity-specific genetic loss-of-function models of the cardiomyocyte-enriched class IIa HDAC family member HDAC4 and the pharmacological class IIa HDAC-selective inhibitor TMP195 prevent and reverse diastolic dysfunction and exercise intolerance in cardiometabolic HFpEF in vivo. In contrast to pan-HDAC inhibition no adverse effects are observed. Despite its well-known non-enzymatic role as transcriptional repressor, we found that specifically enzymatic activation of HDAC4 has little direct effects on cardiomyocyte-intrinsic gene expression. Instead, non-epigenetic actions lead to endothelial activation via altered cardiocrine signaling. We discovered that selective enzymatic class IIa HDAC inhibition is a new therapeutic concept to combat cardiac HFpEF.

molecular biology↗

bioRxiv2026

Multicellular signaling and partial recovery define reverse cardiac remodeling

Heart failure results from maladaptive multicellular remodeling triggered by sustained biomechanical stress. Although mechanical unloading can promote reverse remodeling, recovery is frequently incomplete and its mechanistic basis remains unclear. Using a reversible murine pressure-overload model combined with bulk and single-nucleus transcriptomics, we demonstrate that reverse remodeling represents an actively maintained yet constrained multicellular state. Unloading improved cardiac function and partially restored extracellular matrix and metabolic programs, whereas inflammatory and mitochondrial dysfunction signatures persisted. Cardiomyocytes and endothelial cells largely re-established homeostatic transcriptional states, while fibroblasts retained activated programs that dominated residual pathology. Multicellular factor analysis delineated a reversible metabolic stress program and a persistent inflammatory-mitochondrial program coordinated across cardiac cell types. Cell-cell communication analysis identified lymphatic endothelial cells as key instructive regulators of recovery. Notably, lymphatic-derived Reelin directly suppressed pathological fetal gene activation in murine and human cardiomyocytes, uncovering a previously unrecognized lymphoangiocrine mechanism that constrains myocardial recovery in chronic heart failure.

molecular biology↗

bioRxiv2025

Genomic G quadruplexes regulate mRNA splicing

Genomic G quadruplexes (G4) are non-canonical DNA structures that regulate gene expression primarily through transcriptional control. Here, we uncover that DNA G quadruplexes are critical determinants of pre-mRNA splicing. G4s on the DNA template strand serve as recruiting elements for the RNA-binding proteins SRSF9 and WBP11 in order to facilitate productive splicing of adjacent pre-mRNAs. This process is controlled by protein arginine methyltransferase 5 (PRMT5) that releases SRSF9 and WBP11 from G4s through arginine methylation. Acyl-CoA dehydrogenase very long-chain specific (ACADVL) is a gene highly regulated by this mechanism since targeting G4 stability prevents mis-splicing and restores ACADVL protein levels. In the heart, deletion of Prmt5 recapitulates defective splicing and results in progressive cardiac failure along with loss of ACADVL in mice. Importantly, we find that Acadvl regulation plays a critical role for cardiomyopathy as restoring Acadvl expression in Prmt5 knockout mice prevents cardiac dysfunction. This study establishes an unanticipated fundamental principle by which genomic G quadruplexes act as splicing enhancers of associated pre-mRNAs, and reveals an essential role in cardiac homeostasis.

cell biology↗

bioRxiv2025

CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction (HFrEF) is marked by a shift in cardiac energy metabolism from fatty acid oxidation to glucose utilization. This "fuel switch" promotes accumulation of glucose byproducts that modify calcium-handling proteins and impair cardiac function, yet the initiating signals remain unclear. We identify Ca2+/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [18F]FDG-PET imaging showed a six-fold increase in myocardial glucose uptake after pressure overload in control mice, but not in cardiomyocyte-specific Camk2d/Camk2g double knockouts (cDKO), even before functional decline. cDKO hearts retained lipid reserves, indicating preserved fatty acid metabolism. Transcriptomics revealed strong CAMK2-dependent induction of Nr4a1 and early repression of genes for fatty acid uptake and {beta}-oxidation preceding upregulation of genes for glucose utilization. Cardiomyocyte-specific Nr4a1 knockout mice closely mimicked the metabolic protection seen in cDKO, while NR4A1 overexpression in human iPSC-derived cardiomyocytes suppressed fatty acid metabolism. NR4A1 directly bound and repressed the FATP1 (Slc27a1) promoter, thereby secondarily enhancing glucose utilization. Together, these findings define a CAMK2-NR4A1 signaling axis that drives lipid depletion and metabolic remodeling, establishing it as a causal mechanism linking energy substrate switching to HFrEF.

physiology↗

bioRxiv2025

CAMK2D causes heart failure in RBM20 cardiomyopathy

Although heart disease can arise from different etiologies, current treatment is not tailored to the different underlying causes but is rather a one-size-fits-all approach. Importantly, not all patients benefit from this treatment regimen, which means the number needed to treat is very high. Moreover, this makes clinical trials large and costly, limiting clinical translation. Thus, there is a high medical need to develop a first etiology-specific therapy. Mutations in RBM20, a splicing factor that targets multiple pivotal cardiac genes including TTN and CAMK2D, cause a clinically aggressive form of dilated cardiomyopathy (DCM) with a high risk of malignant ventricular arrhythmias. Here, we hypothesized that CAMK2D is the heart disease-causing target of RBM20. We crossed Camk2d- to Rbm20-deficient mice and found that double knockout (DKO) mice were protected from heart failure and sudden cardiac death. Phosphorylation of multiple CAMK2D targets was increased in Rbm20-deficient mouse hearts, which was reverted in DKO hearts, confirming that CAMK2D is not only misspliced but also overactivated. AAV9-mediated re-expression of single CAMK2D splice variants in DKO mice reintroduced cardiac dysfunction irrespective of the splice variant, unmasking that overactivation rather than missplicing underlies the detrimental phenotype. To test whether heart failure could pharmacologically be reversed, we treated heterozygous Rbm20-R636Q knock-in (KI) mice with hesperadin, a potent CAMK2 inhibitor, which rescued both cardiac function and ventricular geometry. These data demonstrate that overactivation of CAMK2D underlies heart failure in RBM20 cardiomyopathy. Pharmacological inhibition of CAMK2D could therefore become the first cause-directed DCM therapy.

molecular biology↗

bioRxiv2024

Transverse Aortic COnstriction Multi-omics Analysis (TACOMA) uncovers pathophysiological cardiac molecular mechanisms

Time-course multi-omics data of a murine model of progressive heart failure induced by transverse aortic constriction (TAC) provide insights into the molecular mechanisms that are causatively involved in contractile failure and structural cardiac remodelling. We employ Illumina-based transcriptomics, Nanopore sequencing, and mass spectrometry-based proteomics on samples from the left ventricle (LV) and right ventricle (RV, RNA only) of the heart at 1, 7, 21, and 56 days following TAC and Sham surgery. Here, we present TACOMA, as an interactive web-application that integrates and visualizes transcriptomics and proteomics data collected in a TAC time-course experiment. TACOMA enables users to visualize the expression profile of known and novel genes and protein products thereof. Importantly, we capture alternative splicing events by assessing differential transcript and exon usage as well. Co-expression-based clustering algorithms and functional enrichment analysis revealed overrepresented annotations of biological processes and molecular functions at the protein and gene levels. To enhance data integration, TACOMA synchronizes transcriptomics and proteomics profiles, enabling cross-omics comparisons. With TACOMA (https://shiny.dieterichlab.org/app/tacoma), we offer a rich web-based resource to uncover molecular events and biological processes implicated in contractile failure and cardiac hypertrophy. For example, we highlight: (i) changes in metabolic genes and proteins in the time course of hypertrophic growth and contractile impairment; (ii) identification of RNA splicing changes in the expression of Tpm2 isoforms between RV and LV; and (iii) novel transcripts and genes likely contributing to the pathogenesis of heart failure. We plan to extend these data with additional environmental and genetic models of heart failure to decipher common and distinct molecular changes in heart diseases of different aetiologies. Database URLhttps://shiny.dieterichlab.org/app/tacoma

bioinformatics↗

bioRxiv2023

Genetic Loss of Nicotinamide Nucleotide Transhydrogenase Prevents from Cardiometabolic Heart Failure with Preserved Ejection Fraction

RationaleHeart failure with preserved ejection fraction (HFpEF) represents a common clinical endpoint of cardiometabolic diseases which impair myocardial diastolic relaxation. Although myocardial redox perturbations are known to accompany HFpEF, the specific role of mitochondrial oxidative stress has not been demonstrated yet. ObjectiveBased on an observation that C57BL6/N - but not C57BL6/J - mice develop diastolic dysfunction when provided an ad libitum high-fat and 0.5% N({omega})-nitro-L-arginine methyl ester (HFD+L-NAME) diet, we conducted a multi-cohort murine study to determine whether the loss of Nicotinamide Nucleotide Transhydrogenase (NNT), a mitochondrial transhydrogenase that couples NADPH:NADP+ to NADH:NAD+ homeostasis, protects mice from developing cardiometabolic alterations. Methods and ResultsTwo cohorts of 12-week-old male and female mice possessing wild-type (Nnt+/+) or deleted (Nnt-/-) NNT were challenged by HFD+L-NAME for 9 weeks (n = 6-10). Male Nnt+/+ mice developed obesity (23.2% {Delta}, P = 0.003), arterial hypertension (24 {+/-} 5 {Delta} mmHg, P = 0.023), impaired glucose tolerance (P = 0.006), and reduced maximal treadmill running distance (-172 {+/-} 73.1 {Delta} m, P = 0.006) following 9 weeks HFD+L-NAME, whereas male Nnt-/- mice did not. Female mice were protected from cardiometabolic dysfunction regardless of Nnt genotype. Cardiac functional and morphologic characterization revealed similar NNT-dependent and sex-specific increases in E/e (42.8 vs. 21.5, P < 0.001) and E/A (2.3 vs 1.4, P = 0.007) ratios, diastolic stiffness (0.09 vs 0.04 mmHg/L, P = 0.02), and myocardial fibrosis (P = 0.02). Unsupervised transcriptomic analysis identified distinct genetic and dietary signatures, wherein Nnt+/+ exhibited disproportionate perturbations in various mitochondrial oxidative pathways following HFD+L-NAME. Our search for putative transcriptional regulators identified NNT-dependent suppression of NAD+ dependent deacetylase Sirt3. ConclusionsTaken together, these observations support that the genetic disruption of Nnt protects against both cardiac and metabolic consequences of HFD+L-NAME, thus highlighting a novel etiology-specific avenue for HFpEF therapeutics.

physiology↗