Reduced complex n-glycosylation, β-adrenergic receptor sensitivity, and heart failure - heart failure (HF) affects over 64 million people worldwide and remains a leading cause of morbidity, mortality,…

The National Heart, Lung, and Blood Institute awarded Wright State University $552,338 on August 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of reduced complex N-glycosylation in β1-adrenergic receptor sensitivity and heart failure progression.

The research examines whether loss of complex N-glycosylation enhances β1-adrenergic receptor signaling and triggers the transition from compensated to failing myocardium. The project will test this hypothesis across three aims: determining how reduced N-glycosylation accelerates β1-adrenergic receptor-dependent electromechanical dysfunction during disease onset, evaluating whether reduced glycosylation biases β1-adrenergic receptor signaling toward maladaptive stress and remodeling pathways, and identifying the mechanisms connecting these cellular changes to heart failure progression. The work builds on evidence that the glycosyltransferase MGAT1, which initiates complex N-glycan synthesis, is markedly reduced in human end-stage cardiomyopathy, and that cardiomyocyte-specific MGAT1 knockout models show augmented β1-adrenergic receptor-dependent calcium signaling and contractility that produce early hypercontractility, electrical instability, and progressive ventricular dysfunction.

The award runs from August 15, 2026, through April 30, 2029, with work performed in Dayton, Ohio.

Reduced complex n-glycosylation, β-adrenergic receptor sensitivity, and heart failure - heart failure (HF) affects over 64 million people worldwide and remains a leading cause of morbidity, mortality, and healthcare cost. Despite therapeutic advances, current treatments mainly alleviate symptoms rather than target upstream molecular events that initiate disease. Chronic Β₁-adrenergic receptor (Β₁-AR) activation is a hallmark of HF progression, yet the mechanisms that sensitize Β₁-ARS and convert adaptive to maladaptive signaling remain unclear. We propose a new mechanistic concept: loss of complex n-glycosylation enhances Β₁-AR signaling and triggers disease onset. Reduced complex n-glycosylation is linked to aging and cardiovascular disease and may prime cardiomyocytes for Β₁-AR hyperactivation even without excessive sympathetic drive. This would promote early CA2⁺ dysregulation, hypercontractility, and energetic mismatch that initiate HF. The glycosyltransferase MGAT1, which initiates complex n-glycan synthesis, is markedly reduced in human end-stage cardiomyopathy. In cardiomyocyte-specific MGAT1 knockout models, reduced complex n- glycosylation augments Β₁-AR-dependent CA2⁺ signaling and contractility, producing early hypercontractility, electrical instability, and progressive ventricular dysfunction. These findings identify altered glycosylation as an upstream switch that amplifies Β₁-AR activity and accelerates the transition from compensated to failing myocardium. We will test the hypothesis that loss of complex n-glycosylation enhances Β₁-AR signaling, triggering early hypercontractility that precipitates electromechanical dysfunction and accelerates HF progression through three aims: 1) determine how reduced n-glycosylation accelerates Β₁-AR-dependent electromechanical dysfunction during disease onset; 2) determine whether reduced glycosylation biases Β₁-AR signaling toward maladaptive stress and remodeling pathways; and 3) determine whether these mechanisms are conserved in human HF tissue. Mechanistic studies will integrate echocardiography, optical mapping, CA2⁺ imaging, glycomic, and biochemical approaches at molecular, cellular, and organ levels to define how altered glycosylation modifies Β₁-AR signaling and cardiac performance. This project is innovative because IT defines glycosylation as a previously unrecognized regulator of Β₁-AR signaling and cardiac electromechanical activity, linking protein processing to adrenergic signaling and HF onset. Analyses of human ventricular tissue will assess whether these glycosylation-dependent effects are conserved clinically, identifying potential early biomarkers of HF progression. Through mentored participation in molecular, imaging, and physiological studies, students will gain hands-on training in cardiovascular research techniques and data interpretation. These experiences will prepare a new generation of biomedical scientists and expand the research culture at wright state university. The combined scientific and educational impact will strengthen our NIH-funded research foundation and reveal new mechanistic entry points for HF prevention.