Redox activation of JNK2α2 mediates thyroid hormone-stimulated proliferation of neonatal murine cardiomyocytes

Abstract

Mitochondria-generated reactive oxygen species (mROS) are frequently associated with DNA damage and cell cycle arrest, but physiological increases in mROS serve to regulate specific cell functions. T3 is a major regulator of mROS, including hydrogen peroxide (H2O2). Here we show that exogenous thyroid hormone (T3) administration increases cardiomyocyte numbers in neonatal murine hearts. The mechanism involves signaling by mitochondria-generated H2O2 (mH2O2) acting via the redox sensor, peroxiredoxin-1, a thiol peroxidase with high reactivity towards H2O2 that activates c-Jun N-terminal kinase-2α2 (JNK2α2). JNK2α2, a relatively rare member of the JNK family of mitogen-activated protein kinases (MAPK), phosphorylates c-Jun, a component of the activator protein 1 (AP-1) early response transcription factor, resulting in enhanced insulin-like growth factor 1 (IGF-1) expression and activation of proliferative ERK1/2 signaling. This non-canonical mechanism of MAPK activation couples T3 actions on mitochondria to cell cycle activation. Although T3 is regarded as a maturation factor for cardiomyocytes, these studies identify a novel redox pathway that is permissive for T3-mediated cardiomyocyte proliferation—this because of the expression of a pro-proliferative JNK isoform that results in growth factor elaboration and ERK1/2 cell cycle activation.

DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

“…T3-receptor α (TRα) mediates the proliferative action of T3 in murine neonatal (P2) cardiomyocytes by activation of IGF-1/IGF-1R 12 , which involves Ras/Raf/MAPK kinase (MEK)/ERK signaling 9 . MEK1/2 activates ERK1/2 by phosphorylating T202 and Y204 9 , which is required for ERK1/2 translocation to the nucleus 10 .…”

“…Previously, we have shown that exogenous T3 stimulates cardiomyocyte proliferation in P2 murine hearts. These cardiomyocytes are immature and are capable of proliferating in response to growth factors and injury 12 , 17 , 18 . After P6, however, cardiomyocytes do not proliferate in response to injury 18 and are resistant to growth factor-induced cell proliferation 17 .…”

“…We investigated why only a subset of cardiomyocytes, residing at the P8 LV apex, proliferate in response to exogenous T3. Prior studies in neonatal murine cardiomyocytes have shown that T3 proliferative signaling is mediated by increases in IGF-1 and IGF-1R expression 12 . This expression increases growth factor signaling, which phosphorylates and thereby activates the MAP kinases ERK1 and 2.…”

“…This expression increases growth factor signaling, which phosphorylates and thereby activates the MAP kinases ERK1 and 2. Increases in nuclear p-ERK1/2 are required for growth factor-induced cardiomyocyte proliferation, including that due to T3 12 . The rather restricted action of T3 in P8 LV cardiomyocytes is different from the in vivo actions of T3 in neonatal P2 hearts where T3 increases proliferative ERK1/2 signaling in LV cardiomyocytes irrespective of their regional location (Fig.…”

“…We therefore investigated if T3-stimulated ERK1/2 signaling in P8 LV cardiomyocytes is dependent on their spatial location. The T3 proliferative effect is mediated through TRα 12 . We found that expression of this receptor, as well as the ability of T3 to stimulate downstream effectors, viz., IGF-1 expression, IGF-1R activation and MEK1/2 phosphorylation (which are MAP kinases that phosphorylate ERK1/2), occur to a similar extent in cardiomyocytes of both the LV apex and base.…”