title: p38α mitogen-activated kinase mediates cardiomyocyte apoptosis induced by palmitate.
abstract: BACKGROUND
  The mechanisms underlying lipotoxic/diabetic cardiomyopathy remain poorly understood. Saturated fatty acid (SFA) levels, elevated in obesity and type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. Signaling pathways, including the p38α mitogen-activated kinase (MAPK)-dependent pathway, have been implicated in apoptosis due to a diverse range of insults.
  
  
  OBJECTIVE
  We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38α activation.
  
  
  RESULTS
  Human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of palmitate (PA), a SFA. The apoptotic response was measured using annexin-V by flow cytometry, and the p38α-dependent pathway was evaluated using a p38 inhibitor PD169316, and by p38α small interfering RNA (siRNA) knockdown. PA exposure for 16 h dose-dependently increased apoptosis in AC16 cardiomyocytes (control: 2.6±0.6%, 150 μM PA: 3.5±0.9%, 300 μM PA: 11.5±1.6%, n=4, p<0.01). PA did not change total p38α protein levels, but increased p38α phosphorylation dose-dependently (n=5, p<0.01). PD169316 tended to reduce PA-induced apoptosis (n=4, p=0.05). Specific p38α siRNA markedly reduced the expression of p38α but not p38β (n=3, p<0.0001), and dose-dependently attenuated PA-induced apoptosis (control siRNA: 7.7±1.0%, 300 μM PA: 34.4±5.0%, 300 μM PA+30 pmol siRNA: 23.7±4.4%, 300 μM PA+60 pmol siRNA: 19.7±2.6%, 300 μM PA+120 pmol siRNA: 17.3±2.8%, n=4, p<0.0001).
  
  
  CONCLUSIONS
  These results demonstrate that PA induces p38α activation, and reducing p38α expression attenuates PA-induced cardiomyocyte apoptosis. Our results support a potential mechanism by which high plasma SFA levels through p38α activation may lead to the development of lipotoxic/diabetic cardiomyopathy.
authors.affiliation: Phoenix VA HealthCare System, Phoenix, AZ, United States. Electronic address: charles.oh@va.gov.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Oh
authors.affiliation: Phoenix VA HealthCare System, Phoenix, AZ, United States.
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Nguy
authors.affiliation: Phoenix VA HealthCare System, Phoenix, AZ, United States.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Schwenke
authors.affiliation: Phoenix VA HealthCare System, Phoenix, AZ, United States.
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
authors.affiliation: Oregon Health and Science University, 3181 Sam Jackson Park Rd, Portland, OR 97239, United States.
authors.forename: Kent
authors.initials: K
authors.lastname: Thornburg
authors.affiliation: Phoenix VA HealthCare System, Phoenix, AZ, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Reaven
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D019308:Palmitic Acid / Q000008:administration & dosage*
chemical_list: D019308:Palmitic Acid; D048308:Mitogen-Activated Protein Kinase 14
keywords: Apoptosis; Cardiomyopathy; Diabetes; Lipotoxic; p38α MAPK