CaMKII Splice Variants in Vascular Smooth Muscle Cells: The Next Step or Redundancy?

Figures

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  Figure 1. The regulatory mechanisms of vascular smooth muscle cell migration and proliferation. Potential up- and down-regulatory mechanisms of vascular smooth muscle cell migration (VSMC) involving both CaMKII-dependent and -independent mechanisms at both transcriptional and post-transcriptional levels. CaMKIIγ expression and activation leads to promotion of VSMC proliferation and migration, both directly and indirectly, through p21 and p53 cell cycle inhibitors. CaMKIIδ expression leads to increased VSMC migration and proliferation. PKCδ and PDGF both upregulate CaMKIIδ to increase VSMC migration and proliferation. PKCδ works by upregulating ERK1/2 activity via ATP, leading to increased CaMKIIδ activity. PDGF acts directly and indirectly via ERK1/2 to upregulate CaMKIIδ, leading to VSMC migration and proliferation. MCU expression is upregulated by MICU1 and EMRE, leading to the promotion of VMSC migration and proliferation. MMP-9 is upregulated by CaMKIIδ and ERK1/2, leading to increased VSMC migration and proliferation, while eNOS downregulates MMP-9. eNOS further downregulates MMP-2 and upregulates the tissue inhibitor of metalloproteinases 2 (TIMP2) to decrease VSMC migration and…

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  Figure 2. Phenotypic switch of human coronary artery smooth muscle cells (HCASMCs). Atherosclerotic-mimic conditions (150 µM H2O2 and 40 ng/ mL TNF-α) trigger a phenotypic shift from the contractile to synthetic form: (A) representative photograph of HCASMCs under control conditions, exhibiting a classical contractile, elongated shape; (B) representative photograph of HCASMCs under atherosclerotic conditions, exhibiting a classical synthetic, rhomboid shape. Scale bar represents 50 µm.

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  Figure 3. Pathological mechanisms of VSMC hypertrophy. Angiotensin II (AngII) leads to phosphorylation of HDAC4/5 chaperone 14-3-3 binding sites through CaMKII-dependent (HDAC4) and CaMKII-independent (HDAC5) mechanisms. Under physiological conditions, HDAC4/5 forms complexes with myocyte enhancer factor-2 (MEF2). Under pathological conditions, complex formation is downregulated and MEF2 leads to activation of hypertrophic genes for contractile proteins such as beta-MHC, atrial natriuretic factor (ANF), and transcription factor KLF5, leading to VSMC hypertrophy.