Vascular complications associated with diabetes mellitus (DM) have been linked to activation of PKC-dependent signaling pathways in both human and animal models of DM. To determine whether aberrant PKC signaling mechanisms specifically impact the coronary circulation, we assessed isolated coronary artery (CA) responses after the induction of Type 1 DM. Male Sprague-Dawley rats were subjected to partial pancreatectomy (DM; n = 23) and compared with age-matched controls (CTL; n = 19). Vasoreactivity was assessed in single CAs (∼250 μm internal diameter) after abluminal administration of the G q-dependent vasoconstrictors endothelin (ET)-1 (10 -10-10-9 M) and U-44619 (10-9-10-5 M) or the voltage-gated Ca2+ channel agonist BAY K 8644 (10 -9-10-5 M) with and without the PKC inhibitor bisindolylmaleimide (Bis; 10-6 M). Dilator responses to ACh (10 -9-10-5 M) were also assessed. ET-1 resulted in significantly greater constriction in the DM versus CTL group (50 ± 4% vs. 33 ± 5%, P < 0.0001), whereas responses to U-44619 and BAY K 8644 were similar between groups. Importantly, inhibition of ET-1 and U-44619 constriction by Bis occurred in the DM but not CTL group (P < 0.05). Western blotting on isolated CAs revealed greater levels of PKC-α, of PKC-βI, and PKC-βII, by 22%, 15.3%, and 17.6%, respectively, in the DM versus CTL group (P < 0.05), whereas PKC-δ and PKC-ε protein levels were unchanged. DM was also associated with attenuated CA dilation after ACh treatment (P < 0.0566) and reductions in endothelial nitric oxide synthase protein levels versus CTL (P < 0.03). These data suggest that Ca2+-dependent PKC signaling pathways, particularly for ET-1, play a greater role in modulating CA vasoconstrictor responses in DM versus CTL. These data further suggest that aberrant CA constrictor and dilator responses are likely to contribute to the coronary vascular pathology associated with DM.
|Original language||English (US)|
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|Issue number||6 54-6|
|State||Published - Dec 2003|
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
- Physiology (medical)