About

Geert W. Schmid-Schönbein, Ph.D., is a Distinguished Professor of Bioengineering at the University of California, San Diego. His research focuses on microcirculation and the Autodigestion Hypothesis, exploring topics such as aging, sepsis, shock, metabolic disease, autism, and autodigestion. His work involves studying receptor cleavage, protease activity measurements, and the mechanisms underlying autodigestion processes. As a key figure in the Microcirculation Laboratory, he contributes to advancing understanding of critical physiological and pathological processes related to microvascular function and autodigestion.

Research topics

• Internal medicine
• Anesthesia
• Medicine
• Cardiology

Selected publications

• Enteral protease inhibition mitigates impaired Windkessel function in experimental trauma/hemorrhagic shock

  Physiology · 2023

  • Medicine
  • Anesthesia
  • Cardiology

  Introduction: Trauma/hemorrhagic shock (T/HS) is characterized by systemic hypotension and poor organ perfusion, but despite efforts to improve hemodynamic stability via blood product/fluid therapy and vasopressor interventions, diastolic blood pressure (DBP) and thus, mean arterial pressure (MAP) is often recalcitrant to interventions. Large artery compliance is an important determinant of the Windkessel model of vascular hemodynamics, but its functional status remains unresolved in T/HS. We have previously demonstrated that enteral protease inhibition restores blood pressure (BP) and improves autonomic function and vascular resistance after T/HS. Here, we were interested in determining the impact of enteral protease inhibition on arterial compliance in T/HS. Methods: Male Wistar rats (~400g) were randomly assigned to three groups, corresponding to administered resuscitation: shed whole blood (WB), lactated Ringer’s (LR), and LR with enteral gabexate mesilate treatment (LR+GM). Under anesthesia, animals were subjected to experimental T/HS, established by midline laparotomy and controlled hemorrhage to maintain MAP at 35-40 mmHg for 90 min. Animals were then fluid resuscitated with WB or LR over 120 min to achieve a goal MAP of 65 mmHg. Carotid-femoral pulse wave velocities (PWV) and diastolic decay time constants (τ) were estimated from BP waveforms as measures of arterial compliance. Pressure myography was conducted on excised femoral arteries from T/HS animals and healthy donors to assess passive biomechanical properties, i.e., tissue energy loss. Results: PWV increased by ~15% in all T/HS animals at the end of shock compared to baseline. During and at the end of reperfusion, the untreated LR group continued to display elevated PWV, while the PWV of LR+GM and WB animals decreased significantly and returned closer to baseline values (LR: 12.4% vs LR+GM: 6.43%, p<0.05; vs WB: 5.03%, p<0.01). Diastolic τ was reduced by ~34% by the end of shock in all groups but was improved in WB and LR+GM groups by 2 hours after reperfusion. In contrast, this decrease in τ was exacerbated in the LR-only group (p<0.01 vs LR+GM & WB) through the end of the experiment. Biomechanical biaxial testing revealed pronounced leftward shifts in circumferential tension-strain curves in all T/HS groups, especially in the untreated LR group, as compared to healthy animals. Untreated LR vessels demonstrated significantly greater energy loss compared to those of healthy control vessels (31.5% vs 19.7%, p<0.05). Conclusions: Enteral GM infusion attenuated both the marked increases in PWV and vascular energy loss seen after T/HS, suggesting that impairment in arterial compliance after T/HS may be mediated, in part, by serine proteases. By targeting the modulators of large artery Windkessel function, organ perfusion during diastole can be maintained to improve hemodynamic stability and clinical outcomes in T/HS. Department of Defense Award W81XWH-17-2-0047 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

  PublisherDOI

• Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human neuropeptide Y2 receptor promoter disrupt multiple transcriptional response motifs

  UNC Libraries · 2020-11-04

  articleOpen access

  The neuropeptide Y2 G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10 000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter.

  PublisherDOI

• Evaluation of Different Decellularization Protocols on the Generation of Pancreas-Derived Hydrogels

  Tissue Engineering Part C Methods · 2018-11-06 · 82 citations

  articleOpen access

  Different approaches have investigated the effects of different extracellular matrices (ECMs) and three-dimensional (3D) culture on islet function, showing encouraging results. Ideally, the proper scaffold should mimic the biochemical composition of the native tissue as it drives numerous signaling pathways involved in tissue homeostasis and functionality. Tissue-derived decellularized biomaterials can preserve the ECM composition of the native tissue making it an ideal scaffold for 3D tissue engineering applications. However, the decellularization process may affect the retention of specific components, and the choice of a proper detergent is fundamental in preserving the native ECM composition. In this study, we evaluated the effect of different decellularization protocols on the mechanical properties and biochemical composition of pancreatic ECM (pECM) hydrogels. Fresh porcine pancreas tissue was harvested, cut into small pieces, rinsed in water, and treated with two different detergents (sodium dodecyl sulfate [SDS] or Triton X-100) for 1 day followed by 3 days in water. Effective decellularization was confirmed by PicoGreen assay, Hoescht, and H&E staining, showing no differences among groups. Use of a protease inhibitor (PI) was also evaluated. Effective decellularization was confirmed by PicoGreen assay and hematoxylin and eosin (H&E) staining, showing no differences among groups. Triton-treated samples were able to form a firm hydrogel under appropriate conditions, while the use of SDS had detrimental effects on the gelation properties of the hydrogels. ECM biochemical composition was characterized both in the fresh porcine pancreas and all decellularized pECM hydrogels by quantitative mass spectrometry analysis. Fibrillar collagen was the major ECM component in all groups, with all generated hydrogels having a higher amount compared with fresh pancreas. This effect was more pronounced in the SDS-treated hydrogels when compared with the Triton groups, showing very little retention of other ECM molecules. Conversely, basement membrane and matricellular proteins were better retained when the tissue was pretreated with a PI and decellularized in Triton X-100, making the hydrogel more similar to the native tissue. In conclusion, we showed that all the protocols evaluated in the study showed effective tissue decellularization, but only when the tissue was pretreated with a PI and decellularized in Triton detergent, the biochemical composition of the hydrogel was closer to the native tissue ECM. Impact Statement The article compares different methodologies for the generation of a pancreas-derived hydrogel for tissue engineering applications. The biochemical characterization of the newly generated hydrogel shows that the material retains all the extracellular molecules of the native tissue and is capable of sustaining functionality of the encapsulated beta-cells.

  PublisherOA PDFDOI

• Clinical Biomarkers of Congestive Heart Failure Significantly Correlate with Pancreatic Trypsin and Lipase Levels in Human Blood Plasma

  The FASEB Journal · 2018-04-01

  articleSenior author

  We recently have shown that pancreatic enzymes entering the circulation after a rise in intestinal permeability may cause multiple organ dysfunctions. Increased intestinal permeability occurs in congestive heart failure (CHF), for example due to reduction of cardiac output with hypoperfusion of the small intestine. We hypothesize that elevated intestinal permeability during CHF allows digestive enzymes, such as pancreatic trypsin and lipase, typically found in the lumen of the small intestine, to enter the systemic circulation. Our goal is to determine the levels of pancreatic trypsin and lipase and their correlation with clinical biomarkers of inflammation, and functional measurements of the heart and sympathetic nervous system. Blood from 35 (19 CHF and 16 non‐CHF Controls) patients at rest and analyzed by Western Blot for pancreatic lipase and trypsin and for inflammatory markers by ELISA assays for TNF‐a, IL‐6, BNP, ICAM, p‐Selectin, CRP, differential leukocyte counts and adrenergic sensitivity assays using isoproterenol. Clinical measurements such as age, body weight, BMI, and cardiac ejection fraction were recorded. The results showed significantly higher levels of trypsin, lipase, as well as TNF‐a, IL‐6, BNP, p‐Selectin, CRP, and neutrophil count. No change in monocyte, eosinophil, and basophil counts of CHF patients were seen when compared to Control. There were significant correlations between pancreatic trypsin levels and TNF‐a, BNP, and neutrophil count, and also between pancreatic lipase and TNF‐a, IL‐6, BNP, CRP, p‐Selectin, ejection fraction, neutrophil count, and Isoproterenol response. These results suggest that the protein levels of pancreatic digestive enzymes in the systemic circulation are elevated. The levels correlate with functional metrics of CHF and potentially play key roles as CHF biomarkers and in the analysis of the loss of cardiac function. Support or Funding Information National Institutes of Health Grant GM 85072 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

  PublisherDOI

• Cathepsin B Mediated Degradation of Jejunal Epithelial Tight Junction Proteins during the Early Stage of Hemorrhagic Shock

  The FASEB Journal · 2017-04-01 · 2 citations

  articleSenior author

  Hemorrhagic shock has been strongly linked to intestinal permeability — a hallmark of intestinal epithelial barrier breakdown — whose increase is associated with reduced function of intercellular adhesion proteins. The early effects of hemorrhagic shock (HS) on junctional epithelial proteins and the potential mechanisms of increased intestinal permeability have not been fully investigated. We investigate three junctional proteins responsible for epithelial cell adhesion in the jejunum: Claudin‐3, Occludin, and E‐Cadherin. We also investigate the role of Cathepsin B, an epithelial lysosomal cysteine protease, in the degradation of those adhesion protein. We hypothesize that Cathepsin B cleaves the extracellular domain of the adhesion molecules in HS. 16 Sprague‐Dawley rats were divided into 4 groups of 4 animals: Control, HS (MAP = 35mmHg for 30 min without blood volume reconstitution), HS with enteral pre‐treatment by Golytely as a fluid carrier, and HS with enteral pre‐treatment by Golytely and CA074 (Cathepsin B inhibitor at 15mg/kg). Jejunum was collected for Western Blot and immunohistochemistry of Claudin‐3, Occludin, and E‐Cadherin. Both Western Blot and immunohistochemistry results showed a decrease in levels of Claudin‐3 (HS p‐value: 0.052; HS with Golytely p‐value: 0.026), Occludin (HS p‐value: 0.011; HS with Golytely p‐value: 0.0036), and E‐Cadherin (HS p‐value: 0.013; HS with Golytely p‐value: 0.00137) in HS and HS pretreated with Golytely groups when compared to Control. Addition of Cathepsin B inhibitor resulted in maintenance of junctional proteins in the jejunum after HS. These results indicate that active Cathepsin B is released early during HS and causes a reduction of cell‐cell adhesion proteins Claudin‐3, Occludin, and E‐Cadherin, leading to increased intestinal permeability. Support or Funding Information NIH Grant: GM 85072

  PublisherDOI

• Blood Plasma Concentration and Activity of Pancreatic Lipase, Pancreatic Trypsin, MMP‐9, and Elastase in Congestive Heart Failure

  The FASEB Journal · 2017-04-01

  articleSenior author

  Recent evidence suggests that pancreatic digestive enzymes may be involved in several types of organ dysfunction. This may include heart disease, but no studies exist. We hypothesize that pancreatic trypsin, pancreatic lipase, MMP‐9, and elastase may be present in blood and cardiac muscle in patients with congestive heart failure (CHF). Pancreatic enzymes may leak out of the small intestinal lumen, enter the systemic circulation and, ultimately, cause damage of the heart muscle. Pancreatic proteases, such as trypsin, are capable of activating other proteases, such as MMP‐9. Blood was drawn from 20 patients (10 CHF and 10 non‐CHF patients) while at rest. Western Blots showed a significant increase in plasma pancreatic lipase, trypsin, and MMP‐9 levels for the CHF patients when compared to non‐CHF patients. Activity assay results showed a significant increase in plasma MMP‐2/9 activity levels in CHF compared to non‐CHF patients but no differences in trypsin and elastase activity. These pilot experiments suggest that elevated plasma trypsin, lipase, and MMP‐9 concentrations as well as plasma MMP2/9 activity are correlated with CHF, may play a role in the loss of cardiac function, and may serve as potential biomarkers for CHF. Support or Funding Information NIH Grants: 5 R01 HL073355‐01, GM 85072

  PublisherDOI

• Peptidomic characterization of hemorrhagic shock plasma samples: Effects of tranexamic acid

  Journal of Critical Care · 2017-12-01

  articleOpen access
  PublisherOA PDFDOI

• Heredity and cardiometabolic risk

  Journal of Hypertension · 2012-11-16 · 10 citations

  articleOpen access

  OBJECTIVES: The neuropeptide Y(2) G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10,000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter. METHODS AND RESULTS: Twin pair studies indicated substantial heritability for multiple cardiometabolic traits, including BMI, SBP, DBP, and PYY, an endogenous agonist at NPY2R. Systematic polymorphism discovery by resequencing across NPY2R uncovered 21 genetic variants, 10 of which were common [minor allele frequency (MAF) >5%], creating one to two linkage disequilibrium blocks in multiple biogeographic ancestries. In vivo, NPY2R haplotypes were associated with both BMI (P = 3.75E-04) and PYY (P = 4.01E-06). Computational approaches revealed that proximal promoter variants G-1606A, C-599T, and A-224G disrupt predicted IRF1 (A>G), FOXI1 (T>C), and SNAI1 (A>G) response elements. In neuroendocrine cells transfected with NPY2R promoter/luciferase reporter plasmids, all three variants and their resulting haplotypes influenced transcription (G-1606A, P < 2.97E-06; C-599T, P < 1.17E-06; A-224G, P < 2.04E-06), and transcription was differentially augmented or impaired by coexpression of either the cognate full-length transcription factors or their specific siRNAs at each site. Endogenous expression of transcripts for NPY2R, IRF1, and SNAI1 was documented in neuroendocrine cells, and the NPY2R mRNA was differentially expressed in two neuroendocrine tissues (adrenal gland, brainstem) of a rodent model of hypertension and the metabolic syndrome, the spontaneously hypertensive rat. CONCLUSION: We conclude that common genetic variation in the proximal NPY2R promoter influences transcription factor binding so as to alter gene expression in neuroendocrine cells, and consequently cardiometabolic traits in humans. These results unveil a novel control point, whereby cis-acting genetic variation contributes to control of complex cardiometabolic traits, and point to new transcriptional strategies for intervention into neuropeptide actions and their cardiometabolic consequences.

  PublisherOA PDFDOI

• Neuroendocrine Transcriptome in Genetic Hypertension

  Hypertension · 2004-04-20 · 35 citations

  articleOpen access

  The genetic basis of hypertension in the genetically/hereditary hypertensive (BPH/2) mouse strain is incompletely understood, although a recent genome scan uncovered evidence for several susceptibility loci. To probe the neuroendocrine transcriptome in this disease model, 12 488 probe set microarray experiments were performed on mRNA transcripts from adrenal glands of juvenile (prehypertensive) and adult BPH/2 (hypertensive), as well as the genetically/hereditary low-blood pressure (BPL/1), strains at both time points. To determine the impact of strain (BPH/2 versus BPL/1), age (juvenile versus adult), and the interaction of strain and age on gene expression levels, we performed standard 2-factor ANOVA and computed a concordance coefficient to assess the reproducibility of gene expression measurements among replicates. Of genes with significant (P<0.05) differential expression, 2647 showed strain differences, 982 showed age differences, and 757 exhibited strain-by-age interaction. Fold-changes in gene expression assayed by microarray were confirmed in a subset by real-time polymerase chain reaction (R=0.739, P=0.0094). We used a systems biology approach to evaluate alterations in contributing biochemical pathways and we statistically quantified these global pathway disturbances using the Kolmogorov-Smirnov goodness-of-fit test. We found widespread, indeed global, alterations in patterns of gene expression in diverse systems of BPH/2: in sympathochromaffin transcripts suggesting increased sympathetic stimulation; in vasoconstrictor/vasodilator systems; global reductions in carbohydrate intermediary metabolism; and increases in oxidative stress, with changes in oxygen radical forming and disposition enzymes. These analyses highlight widespread derangements in diverse physiological pathways, providing multiple avenues for further investigation into the pathogenesis of genetic hypertension.

  PublisherOA PDFDOI

• EVIDENCE FOR THE CREATION OF CYTOTOXIC FACTORS BY PROTEASES IN THE INTESTINAL LUMEN: A POSSIBLE DAMAGE MECHANISM IN SHOCK.

  Shock · 2003-06-01

  articleSenior author

  Dept. of Bioengineering, Whitaker Institute for Bioengineering, Univ. Calif. San Diego. 9500 Gilman Dr.; La Jolla, CA 92093-0412

  PublisherDOI

Frequent coauthors

• Benjamin W. Zweifach

  11 shared

• Asimina Courelli

  UC San Diego Health System

  10 shared

• Vasiliki Courelli

  La Jolla Bioengineering Institute

  8 shared

• Daniel T. O’Connor

  University of California, Davis

  7 shared

• Soraya Aude

  University of California, San Diego

  6 shared

• Roberto Gaetani

  Sapienza University of Rome

  6 shared

• Heinz Strassle

  Sanford Consortium for Regenerative Medicine

  6 shared

• Lea Lara DeMaddalena

  Sanford Consortium for Regenerative Medicine

  6 shared

Labs

• Microcirculation LaboratoryPI

Awards & honors

• Melville Medal from the American Society of Mechanical Engin…
• Poiseuille Gold Medal by the International Society for Biorh…
• Eugene M. Landis Award by The Microcirculatory Society
• member of the National Academy of Engineering
• fellow of the American Heart Association