Abstract 153: Angiotensin II-induced Hypertension Alters Endothelial CaMKII
The endothelial dysfunction associated with arterial hypertension is characterized by a Ca2+ dyshomeostasis resulting in an alteration of the delicate balance between reactive oxygen species (ROS) and nitric oxide (NO). However, the underlying mechanisms remain controversial.
It has been recently suggested that CaMKII, a Ca2+-calmodulin dependent kinase plays an important role in cardiovascular diseases such as diabetes-associated hypertension. Paradoxically, CaMKII also modulates eNOS expression and activity, and is thereby involved in the regulation of endothelial function. Indeed, acting as a Ca2+ sensor, CaMKII has the unique ability to integrate oscillatory Ca2+ signals into specific outcomes. We recently provided the first evidence that endothelial CaMKII is activated by a local Ca2+ signal, the Ca2+ pulsars, localized within myoendothelial projections (MEP), and results in an increased NO production. The characterization of this novel endothelial CaMKII signalling pathway in pathophysiological conditions will strengthen our understanding of endothelial dysfunction associated with hypertension.
This study aimed at the characterization of the impact of AngII-induced hypertension on the correlation between endothelial Ca2+pulsars and CaMKII in microvasculature.
Real-time confocal imaging showed that acute exposure to AngII (10 μM) increases both ROS intracellular levels (52%) and Ca2+ pulsars frequency (35%). Exposure to lower AngII levels (100 nM) only increased Ca2+ pulsars frequency (49%). However, CaMKIIα and β clustering (and activation) within MEP was observed at both AngII levels. Acute AngII also stimulated NO production (42%), an increase blunted by CaMKII inhibition with KN-93 (17%). Although a significant increase in Ca2+ pulsars frequency was observed (147%) in AngII-hypertensive mice, an AngII-induce increased in endothelial ROS levels was recorded independently of blood pressure levels. Recruitment of CaMKIIα and β at the MEP by chronic AngII was also increased regardless of blood pressure (60% and 43%). Our finding strongly suggests that AngII stimulates CaMKII through both ROS and Ca2+ pulsars . This study consolidates our understanding of CaMKII as a key regulatory component of endothelial function.
- © 2013 by American Heart Association, Inc.