Abstract
BackgroundThe mechanism of cardiac energy production against sustained pressure overload remains to be elucidated.Methods and ResultsWe generated cardiac-specific kinase-dead (kd) calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) transgenic (α-MHC CaMKKβkd TG) mice using α-myosin heavy chain (α-MHC) promoter. Although CaMKKβ activity was significantly reduced, these mice had normal cardiac function and morphology at baseline. Here, we show that transverse aortic binding (TAC) in α-MHC CaMKKβkd TG mice led to accelerated death and left ventricular (LV) dilatation and dysfunction, which was accompanied by significant clinical signs of heart failure. CaMKKβ downstream signaling molecules, including adenosine monophosphate-activated protein kinase (AMPK), were also suppressed in α-MHC CaMKKβkd TG mice compared with wild-type (WT) mice. The expression levels of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, which is a downstream target of both of CaMKKβ and calcium/calmodulin kinases, were also significantly reduced in α-MHC CaMKKβkd TG mice compared with WT mice after TAC. In accordance with these findings, mitochondrial morphogenesis was damaged and creatine phosphate/β-ATP ratios assessed by magnetic resonance spectroscopy were suppressed in α-MHC CaMKKβkd TG mice compared with WT mice after TAC.ConclusionsThese data indicate that CaMKKβ exerts protective effects on cardiac adaptive energy pooling against pressure-overload possibly through phosphorylation of AMPK and by upregulation of PGC-1α. Thus, CaMKKβ may be a therapeutic target for the treatment of heart failure.
Highlights
Previous studies determined that a calcium (Ca2+)-mediated signaling cascade resulting from mechanical overload or Gqmediated signaling initiates changes that lead to cardiac hypertrophy through the activation of calcineurin and consequent targeting of nuclear factor of activated T-cells (NFAT) transcription factors
The major findings of this study are as follows: (1) calmodulin-dependent protein kinase kinase-b (CaMKKb) expression was increased in the left ventricle in response to pressure-overload stress by transverse aortic binding (TAC) in WT mice; (2) TAC in a-myosin heavy chain (a-MHC) CaMKKbkd TG mice resulted in a significant inhibition of CaMKKb downstream signaling molecules, including AMPK, compared with those in WT mice and led to accelerated cardiac dysfunction, which was accompanied by signs of significant clinical heart failure and death; and (3) the expression levels of PGC-1a, which is a downstream target of both of CaMKKb and calmodulin kinase (CaMK), were significantly reduced in aMHC CaMKKbkd TG mice compared with WT mice after TAC
In accordance with these findings mitochondrial morphogenesis was damaged and PCr/b-ATP ratios assessed by Magnetic resonance (MR) spectroscopy were suppressed in a-MHC CaMKKbkd TG mice compared with WT mice after TAC
Summary
Previous studies determined that a calcium (Ca2+)-mediated signaling cascade resulting from mechanical overload or Gqmediated signaling initiates changes that lead to cardiac hypertrophy through the activation of calcineurin and consequent targeting of nuclear factor of activated T-cells (NFAT) transcription factors. There is a lack of knowledge whether there is a signaling mechanism to compensate for cardiac energy production against sustained pressure load. CaMK kinases (CaMKKs) initiate the signaling cascade by phosphorylation and activation of two CaMKs, CaMKI and CaMKIV, whereas CaMKII can be activated by Ca2+/CaM without the activation of CaMKK [3]. CaMKI and CaMKIV require phosphorylation on an activation loop Thr by CaMKKa or CaMKKb. In addition to its role in these enzymatic cascades, CaMKKb is a physiologically relevant upstream activator of adenosine monophosphate (AMP)-activated protein kinase (AMPK); this CaMKKb-AMPK complex is known to regulate the energy balance by acting in the hypothalamus [6]. It is possible that CaMKKb in the heart exerts its role to compensate cardiac energy production against Ca2+ overload induced by sustained pressure load. The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
