Biology subjects

Kobeck, E.

Publications and source records attributed to Kobeck, E..

3 recordsLinked to original sources

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↗