Regulation of Pyruvate Kinase M2 (PKM2) Expression and Activity in Cardiac Hypertrophy
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BACKGROUND: Cardiac hypertrophy is characterized by robust structural, metabolic, and signaling events, which include increased myocyte size and width, increased glycolytic flux, aerobic glycolysis, and induction of transcriptional programs governed by such factors as c-Myc, Fos, and Jun. We have noted that this phenotypic profile exhibits similarities to cancer, where c-Myc, HIF-1α and PKM2 contribute to tumorigenesis and enhanced cancer cell survival in the setting of oxidative stress. PKM2, highly expressed in heart, is the sole pyruvate kinase M isoform expressed in a variety of tumors and is thought to participate in shifts between anabolic and catabolic flux in glycolysis. METHODS AND RESULTS: First, we set out to determine mechanisms underlying aerobic glycolysis in cardiac hypertrophy. We hypothesized that hypertrophic growth cues, including hypoxia, mediate increases in PKM2 protein levels and oxidation at Cys-358. To test this, we first measured protein levels and activity of glycolytic PKM2 in neonatal rat ventricular myocytes maintained in culture. We evaluated four pro-growth stimuli: phenylephrine, endothelin-1, angiotensin II, and hypoxia. We observed that phenylephrine and angiotensin II did not increase normalized PKM2 protein levels, whereas hypoxia and endothelin-1 did. None of these growth stimuli increased PKM2 fractional oxidation. Further, no change in fractional oxidation of PKM2 was observed in mouse hearts subjected to one week of TAC (thoracic aortic constriction). However, an increase in total normalized PKM2 oxidation was readily detected. CONCLUSIONS: Together, these data suggest that hypoxia increases PKM2 protein levels via mechanisms mediated in part by localized ET-1 signaling. Additionally, these data suggest that TAC triggers an increase in the abundance of oxidized PKM2, mediated in part by increased PKM2 protein production. Finally, as phenylephrine did not increase PKM2 oxidation, this suggests that a non-NOX2-dependent mechanism is involved.