BMI- and Gender-specific Increase of MAP2K3/p38 Activity in Human Cardiac Hypertrophy

Introduction: MAP2K3 is a stress-induced kinase and its role cardiac hypertrophy has been controversial: while in vitro studies have displayed a positive correlation in activity with hypertrophy, in vivo studies have shown a negative association. Its direct downstream target, p38α MAPK, has been shown to be in activated in hypertrophic and failed hearts, but this has not been explored with regard to gender or BMI. Hypothesis: Early activation of p38 MAPK in hypertrophy is influenced by gender and BMI. Methods: Human heart samples were grouped into non-failed (NF), left ventricular hypertrophy (LVH), and NF without LVH (control). BMI < 25 was considered “lean”, 25 < BMI < 30 was considered overweight, and BMI > 30 was considered “obese”. RNA-Seq was used to generate cardiac gene expression profiles. Immunoblots were used to examine protein expression of MAP2K3, p38, and activated p38 (pp38; phospho-T180 and Y182). Results: We found that MAP2K3 mRNA levels were increased in obese males by 134% with LVH compared to non-LVH controls (FPKM: LVH = 19.2±3.5, n=3; non-LVH = 8.2±1.9, n=3; FPKM = Fragments Per Kilobase of transcript per Million mapped reads), without statistical significance (p>0.05). MAP2K3 protein expression was 5-fold higher in LVH (1.24±0.20, n=9) versus non-LVH hearts (0.25±0.03, n=15) (p<0.0001). Within all LVH hearts sampled, MAP2K3 protein expression is higher only in male overweight or obese (1.21±0.22, n=7) over lean (0.52±0.04, n=6) (p<0.05). No differences were detected in gene expression profiles of the four isoforms of p38 and total p38 protein expression levels between LVH and NF groups (p>0.05). Activated-p38 was detected in LVH without failure. Levels of p38 activation are higher in overweight/obese than in lean male group (pp38/p38 ratio: M_BMI>25 = 0.63 ± 0.03 (n=7), M_BMI<25 = 0.41 ± 0.12 (n=3), p<0.05). For BMI>25, levels of activated p38 are also higher in male (0.63 ± 0.03, n=7) than in female (0.08 ± 0.01, n=3) (p<0.0001), independent of LVH. Conclusions: We found increased protein expression of MAP2K3 and phosphorylation of p38 in cardiac hypertrophy positively associated with male obese human hearts.