Vascular neointimal formation and signaling pathway activation in response to stent injury in insulin-resistant and diabetic animals.
Diabetes and insulin resistance are associated with increased disease risk and poor outcomes from cardiovascular interventions. Even drug-eluting stents exhibit reduced efficacy in patients with diabetes. We now report the first study of vascular response to stent injury in insulin-resistant and diabetic animal models. Endovascular stents were expanded in the aortae of obese insulin-resistant and type 2 diabetic Zucker rats, in streptozotocin-induced type 1 diabetic Sprague-Dawley rats, and in matched controls. Insulin-resistant rats developed thicker neointima (0.46+/-0.08 versus 0.37+/-0.06 mm2, P=0.05), with decreased lumen area (2.95+/-0.26 versus 3.29+/-0.15 mm2, P=0.03) 14 days after stenting compared with controls, but without increased vascular inflammation (ED1+ tissue macrophages). Insulin-resistant and diabetic rat vessels did exhibit markedly altered signaling pathway activation 1 and 2 weeks after stenting, with up to a 98% increase in p-ERK (anti-phospho ERK) and a 54% reduction in p-Akt (anti-phospho Akt) stained cells. Western blotting confirmed a profound effect of insulin resistance and diabetes on Akt and ERK signaling in stented segments. p-ERK/p-Akt ratio in stented segments uniquely correlated with neointimal response (R2=0.888, P=0.04) in insulin-resistant and type 1 and 2 diabetic rats, but not in lean controls. Transfemoral aortic stenting in rats provides insight into vascular responses in insulin resistance and diabetes. Shifts in ERK and Akt signaling related to insulin resistance may reflect altered tissue repair in diabetes accompanied by a shift in metabolic:proliferative balance. These findings may help explain the increased vascular morbidity in diabetes and suggest specific therapies for patients with insulin resistance and diabetes.
Jonas
Michael
M
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Edelman
Elazer R
ER
Groothuis
Adam
A
Baker
Aaron B
AB
Seifert
Philip
P
Rogers
Campbell
C
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006943:Hyperglycemia / Q000473:pathology; D007333:Insulin Resistance; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015398:Signal Transduction / Q000502:physiology*; D015607:Stents / Q000009:adverse effects*; D013311:Streptozocin; D058570:TOR Serine-Threonine Kinases; D017539:Tunica Intima / Q000473:pathology*
D011518:Proto-Oncogene Proteins; D013311:Streptozocin; D011494:Protein Kinases; C546845:mTOR protein, rat; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases