Mitogen-activated protein kinases mediate angiotensin II-induced upregulation of AT1 receptors in the brain of heart failure rats .

摘要

Chronic heart failure (HF) is characterized by activation of the renin-angiotensin system (RAS) and increased sympathetic outflow. The brain RAS is upregulated and contributes to the progression of HF. I examined the mechanisms responsible for upregulation of the brain angiotensin type I receptor (AT1-R), the component of brain RAS which mediates the effects of angiotensin II (ANG II). Using molecular biology and immunohistochemical techniques, AT1-R expression was detected in the paraventricular nucleus of hypothalamus (PVN) and the subfornical organ (SFO), two key brain regions that regulate sympathetic drive, blood pressure and body fluid homeostasis. The role of ANG II-stimulated mitogen-activated protein kinases (MAPK) in the AT1-R upregulation in HF was investigated by selectively blocking distinct signaling molecules in this pathway. In addition, the effects of inhibiting MAPK activity on cardiovascular responses and sympathetic drive in HF were examined.; Experimental data were obtained from rats with HF induced by myocardial infarction and normal rats chronically infused with ANGII. The levels of AT 1-R protein, AT1-R mRNA and AT1-R-like immunoreactivity were all significantly increased in the PVN and SFO in HF rats and ANG II-infused rats, compared with control animals. The levels of phosphorylated MAPK p44/42, p38 and JNK in the PVN and SFO were similarly elevated. Chronic intracerebroventricular administration of an AT1-R antagonist, two p44/42 MAPK inhibitors and a c-Jun N-terminal kinase (JNK) inhibitor all significantly reduced AT 1-R expression in the PVN and SFO in HF rats and ANG II-infused rats. Chronic infusion of the p38 MAPK inhibitor did not affect AT1-R expression. Brief intracerebroventricular infusions of the p44/42 MAPK inhibitors lowered arterial pressure, heart rate and renal sympathetic nerve activity in HF rats, but had no effect on lumbar sympathetic nerve activity.; The findings demonstrate that increased ANG II, in HF rats and in normal rats, upregulates its own AT1-R in cardiovascular and autonomic regions of the brain, and that p44/42 MAPK and JNK intracellular signaling pathways play a key role in this process. Activated p44/42 MAPK also appears to contribute to the sustained increase in renal sympathetic excitation in rats with HF.