The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.
You WangSuhong ZhuWentao HeHannah MarchukEva RichardLourdes R DesviatSarah P YoungDwight KoeberlTakhar KasumovXiaoxin ChenGuo-Fang ZhangPublished in: Basic research in cardiology (2024)
Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca -/- (A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca -/- (A138T) mice. Additionally, Pcca -/- (A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.
Keyphrases
- fatty acid
- oxidative stress
- induced apoptosis
- left ventricular
- diabetic rats
- mouse model
- ejection fraction
- end stage renal disease
- endothelial cells
- amino acid
- dna damage
- newly diagnosed
- ischemia reperfusion injury
- chronic kidney disease
- prognostic factors
- metabolic syndrome
- high fat diet induced
- copy number
- peritoneal dialysis
- risk assessment
- skeletal muscle
- induced pluripotent stem cells
- heat shock
- anaerobic digestion