Abstract
Abnormal vascular smooth muscle (VSM) growth is central in the pathophysiology of vascular disease yet fully effective therapies to curb this growth are lacking. Recent findings from our lab and others support growth control of VSM by adenosine monophosphate (AMP)-based approaches including the metabolic sensor AMP-activated protein kinase (AMPK) and cAMP-dependent protein kinase (PKA). Molecular crosstalk between AMPK and PKA has been previously suggested, yet the extent to which this occurs and its biological significance in VSM remain unclear. Considering their common AMP backbone and similar signaling characteristics, we hypothesized that crosstalk exists between AMPK and PKA in the regulation of VSM growth. Using rat primary VSM cells (VSMC), the AMPK agonist AICAR increased AMPK activity and phosphorylation of the catalytic Thr172 site on AMPK. Interestingly, AICAR also phosphorylated a suspected PKA-inhibitory Ser485 site on AMPK, and these cumulative events were reversed by the PKA inhibitor PKI suggesting possible PKA-mediated regulation of AMPK. AICAR also increased PKA activity in a reversible fashion. The cAMP stimulator forskolin increased PKA activity and completely ameliorated Ser/Thr protein phosphatase-2C activity, suggesting a potential mechanism of AMPK modulation by PKA since inhibition of PKA by PKI reduced AMPK activity. Functionally, AMPK inhibited serum-stimulated cell cycle progression and cellular proliferation; however, PKA failed to do so. Moreover, AMPK and PKA reduced PDGF-β-stimulated VSMC migration. Collectively, these results show that AMPK is capable of reducing VSM growth in both anti-proliferative and anti-migratory fashion. Furthermore, these data suggest that AMPK may be modulated by PKA and that positive feedback may exist between these two systems. These findings reveal a discrete nexus between AMPK and PKA in VSM and provide basis for metabolically-directed targets in reducing pathologic VSM growth.
Highlights
Aberrant vascular smooth muscle (VSM) growth is a pivotal mechanism underlying numerous pathologies including the evolution of atherosclerotic plaque, pressure- and/or flow-mediated hypertrophy, stent-induced hyperplasia, and iatrogenic restenosis after intervention (Majesky, 1994; Insull, 2009; Wang et al, 2010)
In spite of many studies aimed at reducing the individual components that make up this activated phenotype, abnormal VSM cells (VSMCs) growth remains a critical contributor to vascular pathology and comprehensive, clinically feasible therapies have yet to be identified
AMPK ENHANCES protein kinase (PKA) ACTIVITY Initial experiments focused on activation of AMPK in primary VSMCs
Summary
Aberrant vascular smooth muscle (VSM) growth is a pivotal mechanism underlying numerous pathologies including the evolution of atherosclerotic plaque, pressure- and/or flow-mediated hypertrophy, stent-induced hyperplasia, and iatrogenic restenosis after intervention (Majesky, 1994; Insull, 2009; Wang et al, 2010). Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that responds to cellular energy depletion and stress by inhibiting many ATP-reducing processes, thereby promoting ATP synthetic processes within the cell (Rubin et al, 2005; Sanders et al, 2007). Phosphorylation of the catalytic alpha domain at Thr 172 has been reported to be essential for full kinase activity (Woods et al, 2003; Hardie, 2007, 2011). Alternate alpha moieties, such as Ser 173 (Djouder et al, 2010) or 485 (Hurley et al, 2006), have been suggested to serve inhibitory functions on AMPK activity.
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