Biology subjects

Kobeck, E.

Publications and source records attributed to Kobeck, E..

5 recordsLinked to original sources

bioRxiv2026

Nox4 Mediates Diastolic Function in a Genetic Model of Pitx2 Haploinsufficiency

Heart failure with preserved ejection fraction (HFpEF) commonly coexists with atrial fibrillation (AF), but shared mechanisms remain unclear. In this study, we hypothesized that Pitx2, a transcription factor located near the strongest genetic locus associated with AF in humans, increases susceptibility to HFpEF-like remodeling. We also sought to understand pathways that might be central to this increased risk. Male and female Pitx2+/- mice and wild-type littermates received 3-week subcutaneous osmotic pump infusion of saline or angiotensin II (Ang II; 500 ng/kg/min). Cardiac structure and function were assessed by echocardiography and catheterization, and functional capacity by exercise treadmill. RNA transcriptomic profiling was performed to identify candidate pathways. In a separate cohort, Ang II-treated mice were randomized to oral GKT136901 (30 mg/kg/day) or vehicle during infusion. After Ang II infusion, Pitx2+/- mice developed exaggerated HFpEF-like changes, including greater left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, elevated left ventricular end-diastolic pressure, and reduced treadmill performance. RNA-seq showed enrichment of metabolic and stress-response pathways with selective upregulation of Nox4, confirmed by RT-qPCR. GKT136901 attenuated structural remodeling, diastolic dysfunction indices, elevated filling pressures, and cardiomyocyte hypertrophy, but did not improve endurance. These findings implicate redox signaling, including Nox4, in AF genetic susceptibility-HFpEF interactions.

cell biology↗

bioRxiv2025

Wnt5a-mediated Adipo-Cardiac Interorgan Communication in HFpEF

BackgroundObesity is an important risk factor in heart failure with preserved ejection fraction (HFpEF), but the precise mechanisms that drive obesity-associated cardiac remodeling are not well understood. Our previous work has shown that increased expression of the natriuretic peptide clearance receptor (Nprc) may drive cardiac remodeling in response to high fat diet. In this study, we hypothesized that Nprc plays a central role in preventing and reversing experimental HFpEF. MethodsNprc knockout mice were generated to induce global, cardiomyocyte-specific, or adipocyte-specific disruption of the Nprc (Npr3) gene. HFpEF was induced by the 2-hit stress of L-NAME and high fat diet. Outcomes measured included echocardiography, exercise endurance, invasive catheterization, and histologic assessment. Differential gene expression in adipocyte Nprc knockout visceral adipose tissue was investigated via bulk RNA sequencing and validated by RT-qPCR and culture of H9C2 cells with or without Wnt5a treatment. Adipocyte-mediated Wnt ligand release was interrupted in vivo via LGK974 injection in mice subjected to HFpEF conditions. ResultsGlobal inducible Nprc knockout prevented and reversed structural, hemodynamic, echocardiographic, and exercise tolerance features of HFpEF. This effect was found to be driven by adipocyte-specific, not cardiomyocyte-specific Nprc expression. Bulk RNA sequencing of adipocyte-specific Nprc knockout in peri-gonadal visceral adipose tissue identified downregulation of several secretory pathways, including Wnt pathways. Wnt5a was identified as one of the most downregulated genes by RNA sequencing and specifically validated by qPCR. Wnt5a exposure increased cardiomyocyte hypertrophy in vitro, and LGK974 (PORCN inhibitor) treatment in vivo decreased circulating Wnt5a levels and improved cardiac remodeling in HFpEF. ConclusionsOur study identifies a novel crosstalk mechanism between cardiomyocytes and adipocytes in obesity-associated HFpEF driven by natriuretic peptide-mediated inhibition of release of Wnt5a from adipocytes.

molecular biology↗

bioRxiv2025

Reducing Reactive Lipids Improves Cardiac Metabolic and Diastolic Function in Pulmonary Hypertension Models

BackgroundReactive oxygen species are increased across most pulmonary hypertension (PH) etiologies, resulting in increased reactive lipid dicarbonyls, which form protein adducts and impair mitochondrial function. We hypothesized that reducing reactive lipids would reduce right ventricular systolic pressure (RVSP) and improve cardiac function by eliminating protein-lipid damage feedback loops. MethodsWe used 2-hydroxybenzylamine (2-HOBA) to scavenge reactive lipids in three complimentary mouse models of PH: AKR-high fat diet (HFD, metabolic stress), LNAME-HFD (cardiometabolic syndrome), and pulmonary artery banding (PAB, load stress). Cardiac function was measured by echocardiography and catheterization. RV energy metabolism was determined by oxygraphy. Mass spectrometry analyzed lipids and ceramides; O-link and RNA-Seq evaluated proteomic and gene expression in lungs, RV, and LV. ResultsReducing reactive lipids with 2-HOBA resulted in a [~]10% reduction in RVSP, reduced diastolic dysfunction, reduced plasma lipids and ceramides, and normalized RV fatty acid oxidation that was severely impaired in the AKR-HFD and PAB models. Proteomic and RNA changes in the lungs, RV, and LV suggested reduced oxidative damage and inflammatory signaling and altered developmental and actin organization signaling; these changes are plausibly associated with the improved adaptation. Some changes were sex specific, including a 4x higher cardiac fatty acid content in males than females. ConclusionsReactive lipid scavenging improves cardiac metabolic and diastolic function and pulmonary vascular resistance through restoration of mitochondrial function and reduced oxidative protein damage. The magnitude of hemodynamic improvement combined with substantial diastolic function improvement suggests clinical potential, particularly for PH patients with metabolic comorbidities.

molecular biology↗

bioRxiv2025

Salt-inducible kinase inhibition promotes weight loss and improves the diastolic function of obesity-related heart failure with preserved ejection fraction in mice

BackgroundObesity negatively impacts cardiac function and is closely associated with heart failure with preserved ejection fraction (HFpEF). Salt-inducible kinases (SIKs) are critical regulators of energy metabolism and cardiovascular function. Small molecule SIK inhibitors have been developed but their effect in treating obesity-related HFpEF remains unexplored. We recently discovered that pharmacological SIK inhibition promotes the adipose tissue thermogenesis and mitochondrial biogenesis gene program. We reason that targeting SIKs to treat obesity-related complications would be beneficial for HFpEF. MethodsWe employed a preclinical HFpEF mouse model induced by two-hit stress of high-fat diet (HFD) and nitric oxide synthase (NOS) inhibition using L-NAME in drinking water. Eight-week-old C57BL/6J mice received a regular low-fat chow diet or HFD/L-NAME for 5 weeks and were treated with vehicle or a pan-SIK inhibitor YKL-05-099 (YKL) via daily intraperitoneal injection in the last 4 weeks. Body weight and parameters of adiposity, energy balance and glucose tolerance were assessed. Cardiovascular function was characterized by echocardiography and in vivo pressure-volume loop hemodynamic analysis. Myocardial transcriptomic data were analyzed to determine if changes in SIK gene expression are associated with human HFpEF. ResultsYKL treatment limits body weight gain mainly by reducing the fat mass in obese HFpEF mice. YKL-treated mice show better glucose tolerance, enhanced adipose tissue browning and decreased lipid deposition. YKL-treatment mice demonstrate preserved left ventricular (LV) ejection fraction, reduced LV filling pressure and improved diastolic function. Myocardial expression of SIK1, SIK2, and SIK3 mRNA is down-regulated in patients with HFpEF. However, higher SIK mRNA expression is associated with a subgroup of HFpEF patients that has a greater risk for HF hospitalization and/or death. ConclusionsTaken together, our study reveals a pathological role for SIKs in obesity-related HFpEF and suggests that pharmacological SIK inhibition would be a disease-modifying strategy for obese HFpEF, for which evidence-based therapy has been limited.

physiology↗

bioRxiv2023

Myeloid Cell-Derived IL1β Contributes to Pulmonary Vascular Remodeling in Heart Failure with Preserved Ejection Fraction

BackgroundPulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are not well understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH in HFpEF, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF. MethodsEight week old male and female C57/BL6J mice were given either L-NAME and high fat diet (HFD) or control water/diet for 2,5, and 12 weeks. Bulk RNA sequencing and single cell RNA sequencing was performed to identify early and cell-specific pathways that might regulate pulmonary vascular remodeling in PH-HFpEF. Finally, clodronate liposome and IL1{beta} antibody treatments were utilized to deplete macrophages or IL1{beta}, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF. ResultsMice given L-NAME/HFD developed PH, small vessel muscularization, and right heart dysfunction after 2 weeks of treatment. Inflammation-related gene ontologies were over-represented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling of mouse lung and plasma showed an increase in IL1{beta}, which was confirmed in plasma from patients with HFpEF. Single cell sequencing of mouse lungs also showed an increase in M1-like, pro-inflammatory populations of Ccr2+ monocytes and macrophages, and transcript expression of IL1{beta} was primarily restricted to myeloid-type cells. Finally, clodronate liposome treatment prevented the development of PH in L-NAME/HFD treated mice, and IL1{beta} antibody treatment also attenuated PH in L-NAME/HFD treated mice. ConclusionsOur study demonstrated that a well-accepted model of HFpEF recapitulates features of pulmonary vascular remodeling commonly seen in patients with HFpEF, and we identified myeloid cell derived IL1{beta} as an important contributor to PH in HFpEF.

cell biology↗