Related Experiment Videos

Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I

Chris Mühlhausen1, Nicola Ott, Fariba Chalajour

  • 1Department of Pediatrics, University of Hamburg, Germany.

Pediatric Research
|January 28, 2006
PubMed

Insights

Glutaric aciduria type 1 (GA1) metabolite 3-hydroxyglutaric acid (3-OH-GA) impairs blood vessel function. This metabolite disrupts endothelial cell migration and vascular integrity, potentially explaining GA1-related vasculopathy.

Area of Science:

  • Biochemistry
  • Vascular Biology
  • Metabolic Disorders

Background:

  • Infants with Glutaric Aciduria Type 1 (GA1) exhibit intracranial vascular dysfunction.
  • The specific metabolite 3-hydroxyglutaric acid (3-OH-GA) is implicated in GA1 pathogenesis.

Purpose of the Study:

  • To investigate the effects of 3-OH-GA on endothelial cell function and vascular integrity.
  • To elucidate the mechanisms underlying 3-OH-GA-induced vasculopathy in GA1.

Main Methods:

  • In vitro studies using endothelial cells to assess migration, tube formation, and actin cytoskeleton.
  • In vivo studies using chick chorioallantoic membrane assay to evaluate vascular responses to 3-OH-GA.

Main Results:

  • 3-OH-GA inhibited basal and VEGF-induced endothelial cell migration and tube formation.
  • 3-OH-GA treatment disrupted endothelial cell morphology, leading to Ve-cadherin loss and actin cytoskeleton disorganization.
  • In vivo, 3-OH-GA induced vascular dilatation and hemorrhage, indicating impaired vascular integrity.

Conclusions:

  • 3-OH-GA significantly impairs endothelial cell chemotaxis and compromises structural vascular integrity.
  • These findings suggest 3-OH-GA plays a critical role in GA1-associated vasculopathic processes.
  • Potential involvement of N-methyl-D-aspartate receptor-dependent and -independent pathways in GA1 pathogenesis is proposed.

Related Concept Videos

Hyperglycemia01:29

Hyperglycemia

Hyperglycemia is an abnormally high blood glucose level. It is diagnosed by fasting glucose ≥126 mg/dL, 2-hour oral glucose tolerance test (or OGTT) ≥200 mg/dL, random glucose ≥200 mg/dL with symptoms, or HbA1c ≥6.5%. However, HbA1c results may be unreliable in certain conditions, such as anemia or hemoglobinopathies, and the diagnosis should be confirmed unless classic symptoms are present. Postprandial hyperglycemia is typically considered significant when glucose levels exceed 180 mg/dL two...
Type I Diabetes III: Clinical Manifestations01:19

Type I Diabetes III: Clinical Manifestations

Type 1 diabetes mellitus typically presents with rapid-onset symptoms due to the body’s inability to utilize glucose in the absence of insulin. Since insulin is required for glucose uptake into cells, its deficiency leads to hyperglycemia and cellular energy deprivation, resulting in characteristic clinical features.Polyuria and PolydipsiaOne of the earliest, most prominent symptoms is polyuria (excessive urination). When blood glucose concentrations rise above the renal threshold, the kidneys...
Diabetic Nephropathy01:28

Diabetic Nephropathy

Definition Diabetic nephropathy is a chronic kidney complication that results from prolonged hyperglycemia.Prevalence It is the most common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide, affecting up to half of individuals with diabetes.Pathophysiology • Sustained hyperglycemia triggers multiple hemodynamic and metabolic changes in the kidney. • Early in the disease, increased renal blood flow and glomerular hyperfiltration occur due to afferent arteriolar...
Glucose Transporters01:27

Glucose Transporters

Glucose transporters facilitate the transport of glucose across the cell membrane. In addition to glucose, some glucose transporters can also aid the movement of other hexoses such as fructose, mannose, and galactose.
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
Type I Diabetes II: Pathophysiology01:26

Type I Diabetes II: Pathophysiology

Type 1 diabetes mellitus arises from an immune-mediated destruction of pancreatic β-cells, resulting in an absolute deficiency of insulin. This process develops in genetically susceptible individuals when autoimmunity, environmental exposures, and immunologic dysregulation converge to trigger a targeted attack on the insulin-producing cells of the pancreas. The β-cells are located within the islets of Langerhans and are essential for regulating blood glucose by facilitating cellular uptake of...
Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase01:27

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...