Hypertension, dyslipidemia, inflammation, impaired fibrinolysis, and hyperglycemia all play a role in the damage done to the vasculature by type 2 diabetes and insulin resistance. In health, vascular smooth muscle cells (SMCs) are quiescent and contractile and have low proliferative and migratory activities. However, in the case of diabetes and metabolic stress, vascular smooth muscle cells undergo a change in phenotype to an increased proliferative and migratory state. This is known as phenotypic modulation and in excess it is the hallmark of atherosclerosis. The transcription factor CREB (cAMP response element binding protein) has been shown to be important for maintenance of the highly differentiated proliferation-resistant phenotype of vascular SMCs by our lab. We have observed early injury-induced activation of CREB in rodent models of atherosclerosis, a presumed early cytoprotective response to injury. The mechanism of CREB activation in this setting is unknown. Recently a novel signaling mechanism mediated by protein kinase N (PKN or PRK1/PRK2) was identified and shown to increase the transcription of SMC contractile proteins in a p38 MAPK dependent fashion. We hypothesized that PKN would increase in response to early vascular injury and activate CREB via phosphorylation. To address this hypothesis we measured protein content by Western blot analysis of PKN in aortic vessel wall lysates from young (4 wk) and old (14 wk) Zucker rats as compared with age-matched control rats. In the 4-week animals, there was a high level of PKN, which was higher in the Zucker animal (OD = 1.61 total PKN) than the control animals (OD = 1.54 total PKN). Overall PKN content decreased with age but remained higher in the Zucker cohort (OD = 1.29 for Zucker vs 0.82 in control animals). Preliminary studies assessing PKN activity (phosphoPKN) indicated than activation paralleled content. These values correlated positively with values of active CREB previously found in the same animals. In summary, expression of PKN decreases with age in the vasculature and its expression is higher in a model of insulin resistance. This is the first in vivo observation of disease-related induction of PKN in response to insulin resistance. Future studies will determine whether PKN directly activates CREB. In conclusion, PKN may be a part of a cytoprotective vascular response to injury that loses effectiveness with age.
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