About

Wolfgang Dillmann is a faculty member at UCSD in the School of Medicine, with research activities focused on heart function, aging, and related cardiovascular conditions. His work involves investigating the molecular mechanisms underlying heart failure, diabetic cardiomyopathy, and cardiac hypertrophy, with particular attention to mitochondrial calcium handling, protein O-GlcNAcylation, and the role of thyroid hormone receptors in cardiac health. His research has contributed to understanding how mitochondrial dysfunction, oxidative stress, and metabolic regulation impact heart disease, especially in the context of diabetes and aging. Throughout his career, Dr. Dillmann has led numerous NIH-funded projects as Principal Investigator, exploring topics such as heart vascular function, thyroid hormone action in the heart, and mitochondrial calcium regulation. His studies employ experimental endocrinology, molecular biology, and physiology to elucidate the pathways involved in cardiac pathophysiology. His work has advanced knowledge on the molecular and cellular basis of heart failure, with implications for developing targeted therapies for cardiovascular diseases related to metabolic and age-related factors.

Research topics

• Medicine
• Endocrinology
• Internal medicine
• Cell biology
• Biology
• Cardiology
• Immunology
• Biochemistry

Selected publications

• Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction

  Cell Metabolism · 2025-04-22 · 9 citations

  articleOpen access
  PublisherOA PDFDOI

• Restoration of coronary microvascular function by OGA overexpression in a high-fat diet with low-dose streptozotocin-induced type 2 diabetic mice

  Diabetes and Vascular Disease Research · 2023-05-01 · 10 citations

  articleOpen access

  Sustained hyperglycemia results in excess protein O-GlcNAcylation, leading to vascular complications in diabetes. This study aims to investigate the role of O-GlcNAcylation in the progression of coronary microvascular disease (CMD) in inducible type 2 diabetic (T2D) mice generated by a high-fat diet with a single injection of low-dose streptozotocin. Inducible T2D mice exhibited an increase in protein O-GlcNAcylation in cardiac endothelial cells (CECs) and decreases in coronary flow velocity reserve (CFVR, an indicator of coronary microvascular function) and capillary density accompanied by increased endothelial apoptosis in the heart. Endothelial-specific O-GlcNAcase (OGA) overexpression significantly lowered protein O-GlcNAcylation in CECs, increased CFVR and capillary density, and decreased endothelial apoptosis in T2D mice. OGA overexpression also improved cardiac contractility in T2D mice. OGA gene transduction augmented angiogenic capacity in high-glucose treated CECs. PCR array analysis revealed that seven out of 92 genes show significant differences among control, T2D, and T2D + OGA mice, and Sp1 might be a great target for future study, the level of which was significantly increased by OGA in T2D mice. Our data suggest that reducing protein O-GlcNAcylation in CECs has a beneficial effect on coronary microvascular function, and OGA is a promising therapeutic target for CMD in diabetic patients.

  PublisherOA PDFDOI

• Hexokinase-1 mitochondrial dissociation and protein O-GlcNAcylation drive heart failure with preserved ejection fraction

  Research Square · 2023-01-25 · 2 citations

  preprintOpen access

  Abstract The authors have requested that this preprint be removed from Research Square as it was inadvertently submitted.

  PublisherDOI

• Gut lumen-leaked microbial DNA causes myocardial inflammation and impairs cardiac contractility in ageing mouse heart

  Frontiers in Immunology · 2023-07-13 · 10 citations

  articleOpen access

  Emerging evidence indicates the critical roles of microbiota in mediating host cardiac functions in ageing, however, the mechanisms underlying the communications between microbiota and cardiac cells during the ageing process have not been fully elucidated. Bacterial DNA was enriched in the cardiomyocytes of both ageing humans and mice. Antibiotic treatment remarkably reduced bacterial DNA abundance in ageing mice. Gut microbial DNA containing extracellular vesicles (mEVs) were readily leaked into the bloodstream and infiltrated into cardiomyocytes in ageing mice, causing cardiac microbial DNA enrichment. Vsig4 + macrophages efficiently block the spread of gut mEVs whereas Vsig4 + cell population was greatly decreased in ageing mice. Gut mEV treatment resulted in cardiac inflammation and a reduction in cardiac contractility in young Vsig4 -/- mice. Microbial DNA depletion attenuated the pathogenic effects of gut mEVs. cGAS/STING signaling is critical for the effects of microbial DNA. Restoring Vsig4 + macrophage population in ageing WT mice reduced cardiac microbial DNA abundance and inflammation and improved heart contractility.

  PublisherOA PDFDOI

• Microbial DNA Enrichment Promotes Adrenomedullary Inflammation, Catecholamine Secretion, and Hypertension in Obese Mice

  Journal of the American Heart Association · 2022 · 14 citations

  • Endocrinology
  • Internal medicine
  • Medicine

  (complement component 3) mice intravenously injected with gut mEVs, adrenal microbial DNA accumulation elevated adrenal inflammation and norepinephrine secretion, concomitant with hypertension. In addition, microbial DNA promoted inflammatory responses and norepinephrine production in rat pheochromocytoma PC12 cells treated with gut mEVs. Depletion of microbial DNA cargo markedly blunted the effects of gut mEVs. We also validated that activation of cGAS (cyclic GMP-AMP synthase)/STING (cyclic GMP-AMP receptor stimulator of interferon genes) signaling is required for the ability of microbial DNA to trigger adrenomedullary dysfunctions in both in vivo and in vitro experiments. Restoring CRIg+ cells in obese mice decreased microbial DNA abundance, inflammation, and hypertension. Conclusions The leakage of gut mEVs leads to adrenal enrichment of microbial DNA that are pathogenic to induce obesity-associated adrenomedullary abnormalities and hypertension. Recovering the CRIg+ macrophage population attenuates obesity-induced adrenomedullary disorders.

  PublisherOA PDFDOI

• Morphine induces physiological, structural, and molecular benefits in the diabetic myocardium

  The FASEB Journal · 2021-02-14 · 13 citations

  articleOpen access

  Abstract The obesity epidemic has increased type II diabetes mellitus (T2DM) across developed countries. Cardiac T2DM risks include ischemic heart disease, heart failure with preserved ejection fraction, intolerance to ischemia‐reperfusion (I‐R) injury, and refractoriness to cardioprotection. While opioids are cardioprotective, T2DM causes opioid receptor signaling dysfunction. We tested the hypothesis that sustained opioid receptor stimulus may overcome diabetes mellitus‐induced cardiac dysfunction via membrane/mitochondrial‐dependent protection. In a murine T2DM model, we investigated effects of morphine on cardiac function, I‐R tolerance, ultrastructure, subcellular cholesterol expression, mitochondrial protein abundance, and mitochondrial function. T2DM induced 25% weight gain, hyperglycemia, glucose intolerance, cardiac hypertrophy, moderate cardiac depression, exaggerated postischemic myocardial dysfunction, abnormalities in mitochondrial respiration, ultrastructure and Ca 2+ ‐induced swelling, and cell death were all evident. Morphine administration for 5 days: (1) improved glucose homeostasis; (2) reversed cardiac depression; (3) enhanced I‐R tolerance; (4) restored mitochondrial ultrastructure; (5) improved mitochondrial function; (6) upregulated Stat3 protein; and (7) preserved membrane cholesterol homeostasis. These data show that morphine treatment restores contractile function, ischemic tolerance, mitochondrial structure and function, and membrane dynamics in type II diabetic hearts. These findings suggest potential translational value for short‐term, but high‐dose morphine administration in diabetic patients undergoing or recovering from acute ischemic cardiovascular events.

  PublisherOA PDFDOI

• Constitutive protein kinase G activation exacerbates stress‐induced cardiomyopathy

  British Journal of Pharmacology · 2021-05-17 · 14 citations

  articleOpen access

  Background and Purpose Heart failure is associated with high morbidity and mortality, and new therapeutic targets are needed. Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventricular remodelling and cardiac dysfunction in the stressed heart. However, clinical trial results have been mixed and the effects of long‐term PKG activation in the heart are unknown. Experimental Approach We characterized the cardiac phenotype of mice carrying a heterozygous knock‐in mutation of PKG1 (Prkg1 R177Q/+ ), which causes constitutive, cGMP‐independent activation of the kinase. We examined isolated cardiac myocytes and intact mice, the latter after stress induced by surgical transaortic constriction or angiotensin II (Ang II) infusion. Key Results Cardiac myocytes from Prkg1 R177Q/+ mice showed altered phosphorylation of sarcomeric proteins and reduced contractility in response to electrical stimulation, compared to cells from wild type mice. Under basal conditions, young PKG1 R177Q/+ mice exhibited no obvious cardiac abnormalities, but aging animals developed mild increases in cardiac fibrosis. In response to angiotensin II infusion or fixed pressure overload induced by transaortic constriction, young PKG R177Q/+ mice exhibited excessive hypertrophic remodelling with increased fibrosis and myocyte apoptosis, leading to increased left ventricular dilation and dysfunction compared to wild type litter mates. Conclusion and Implications Long‐term PKG1 activation in mice may be harmful to the heart, especially in the presence of pressure overload and neurohumoral stress. LINKED ARTICLES This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc

  PublisherOA PDFDOI

• Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

  Diabetes · 2020-05-04 · 70 citations

  letterOpen access

  Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

  PublisherOA PDFDOI

• Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

  2020-05-04 · 4 citations

  preprintOpen access

  Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

  PublisherDOI

• Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

  2020-05-04

  preprintOpen access

  Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by <i>O</i>-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct <i>O</i>-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins.<b> </b>These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

  PublisherDOI

Recent grants

• NIH Grant R37HL049434

  NIH · $3.1M · 2008

• NIH Grant R01HL066917

  NIH · $4.8M · 2013

• NIH Grant R01HL049434

  NIH · $1.2M · 1998

• NIH Grant P01HL066941

  NIH · $35.4M · 2020

• NIH Grant P01HL06694113

  NIH · $5.9M · 2016

Frequent coauthors

• Jorge Suárez

  Veterans Medical Research Foundation of San Diego

  65 shared

• Brian T. Scott

  University of California System

  46 shared

• Ruben Mestril

  University of Chicago

  36 shared

• Patrick M. McDonough

  Andrew McDonough B+ Foundation

  30 shared

• Darrell D. Belke

  University of Calgary

  27 shared

• Ayako Makino

  University of Arizona

  26 shared

• Jack H. Oppenheimer

  University of Minnesota

  24 shared

• Markus Meyer

  Minneapolis Heart Institute Foundation

  23 shared