Angiotensin Receptor Blocker Directly Binds to HSP and Stimulates its Production in the Brain

摘要

Antihypertensive angiotensin II type 1 receptor blockers (ARBs) have neuroprotective effects that were independent of the reduction of blood pressure. We have previously shown that vulnerable hippocampal CA1 neurons underwent delayed cell death through mitochondria-dependent apoptotic pathway after global cerebral ischemia, but ARB protected these neurons from cell death. To elucidate the mechanism of neuroprotection by ARB candesartan, candesartan-specific binding proteins were first investigated using candesartan-affinity column and rat hippocampal tissue. And, the affinity of ARB and the binding protein was further examined by BIAcore binding assay. Then, the distribution and expression of the protein were characterized by immunohisotochemistry and Western blots. By affinity column study, molecular chaperone heat shock protein 90 (HSP90) was identified as a binding target of candesartan. BIAcore assay proved functional binding of candesartan to HSP90. Immunohistochemistry showed increased HSP90 expression in the hippocampal CA1 neurons as early as 1 day after candesartan treatment. Westen blots confirmed temporal changes in HSP90 expression.HSP90 maintains the stability of the proteins as a molecular chaperone and has been recently proven to inhibit apoptosis in in vitro studies. Our data suggest that HSP90 may play an important role in neuronal protection by ARB treatment through blocking mitochondria-dependent apoptosis.