Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC β Inhibitor

Abstract

The vascular complications of diabetes mellitus have been correlated with enhanced activation of protein kinase C (PKC). LY333531, a specific inhibitor of the beta isoform of PKC, was synthesized and was shown to be a competitive reversible inhibitor of PKC beta 1 and beta 2, with a half-maximal inhibitory constant of approximately 5 nM; this value was one-fiftieth of that for other PKC isoenzymes and one-thousandth of that for non-PKC kinases. When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities.

Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion

“…We used tumor mast cells (rat basophilic leukemia cells, RBL‐2H3; Kalesnikoff & Galli, 2008; Wollman & Meyer, 2012) which secrete only part (~30%) of their stored inflammatory agents in response to maximal antigen stimulation (Fig 1A), consistent with the existence of inhibitory pathways that prevent the release of the remaining vesicles. Since previous studies proposed that PKCB is the main PKC isoform regulating mast cell secretion (Nechushtan et al , 2000), we confirmed that inhibition of PKCB with ruboxistaurin (Ishii et al , 1996; Tsai et al , 2014) further reduces the amount of released vesicles in a dose‐dependent manner following stimulation with antigen (Fig 1A) or simultaneous addition of the PKC activators phorbol ester and Ca 2+ ionophore (Fig EV1A).…”

Superoxide as a Messenger of Endothelial Function

“…Adverse effects of elevated glucose levels on acetylcholine-induced relaxation of rabbit aorta and rat pial arterioles were restored by the addition of PKC inhibitors (Mayhan and Patel, 1995;Tesfamariam et al, 1991). These in vitro observations are supported by studies, demonstrating, that in vivo treatment with PKC inhibitors ameliorates vascular complications in diabetic rats (Ishii et al, 1996). Of course signal transduction and intracellular crosstalk by PKC dependent phosphorylation is manifold and complicated.…”

Angiotensin AT 1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

“…Previous studies have shown that treatment of DM rats with an endothelin type A receptor antagonist (BQ123), a PKCβ inhibitor (LY333531), or vitamin E could also ameliorate RBF abnormalities [10,27,30,31]. In addition, intravitreal injections of endothelin-1 or phorbol dibutyrate (an activator of PKC) rapidly induced retinal arteriole constriction and prolonged MCT, which mimicked diabetes [31,32].…”