Angiotensin II Causes Apoptosis of Adult Hippocampal Neural Stem Cells and Memory Impairment Through the Action on AMPK-PGC1α Signaling in Heart Failure

Abstract

Data are limited on the mechanisms underlying memory impairment in heart failure (HF). We hypothesized that angiotensin II (Ang II) may determine the fate of adult hippocampal neural stem cells (HCNs), a cause of memory impairment in HF. HCNs with neurogenesis potential were isolated and cultured from adult rat hippocampi. Ang II decreased HCN proliferation in dose‐ and time‐dependent manners. Moreover, Ang II treatment (1 µM) for 48 hours induced apoptotic death, which was attenuated by pretreatment with Ang II receptor blockers (ARBs). Ang II increased mitochondrial reactive oxygen species (ROS) levels, which was related to mitochondrial morphological changes and functional impairment. Moreover, ROS activated the AMP‐activated protein kinase (AMPK) and consequent peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) expression, causing cell apoptosis. In the HF rat model induced by left anterior descending artery ligation, ARB ameliorated the spatial memory ability which decreased 10 weeks after ischemia. In addition, neuronal cell death, especially of newly born mature neurons, was observed in HF rat hippocampi. ARB decreased cell death and promoted the survival of newly born neural precursor cells and mature neurons. In conclusion, Ang II caused HCN apoptosis through mitochondrial ROS formation and subsequent AMPK‐PGC1α signaling. ARB improved learning and memory behaviors impaired by neuronal cell death in the HF animal model. These findings suggest that HCN is one treatment target for memory impairment in HF and that ARBs have additional benefits in HF combined with memory impairment. Stem Cells Translational Medicine 2017;6:1491–1503

Interaction between Angiotensin Type 1, Type 2, and Mas Receptors to Regulate Adult Neurogenesis in the Brain Ventricular–Subventricular Zone

“…We observed that both AT1 and AT2 receptors were involved in regulation of proliferation of V-SVZ cells ( Figure 8A), and that the expression of AT1 and AT2 receptors (i.e., AT1/AT2 ratio) may be modified by aging, drugs such as AT1 receptor antagonists (candesartan), or species differences ( Figure 8B). The results are consistent with previous studies showing immunoreactivity for AT1 and AT2 receptors in aggregates of precursor cells obtained from developing brain tissue [19], and with a timedependent increase in AT1 and AT2 receptor expression in cultured rat NSCs derived from embryonic and adult hippocampus [68,69]. Using confocal microscopy, we observed that AT1 and AT2 receptors were mostly expressed in V-SVZ neuroblasts.…”

Short-term Heat Exposure Promotes Hippocampal Neurogenesis via Activation of Angiotensin II Type 1 Receptor in Adult Rats

“…However, in an in vitro examination, AT1R activation elicited by chronic (over 24 h) and high dose (over 10 À7 M) application of Ang II was found to directly induce apoptosis of cultured hippocampal neural stem cells isolated from rats (Kim et al, 2017). Also, it has been shown that heart failure elicits AT1Rmediated cell death of newborn hippocampal neurons in rats (Kim et al, 2017). In the present study, however, we did not observe a decrease in neuronal progenitors or newborn neurons.…”

“…Taken together, these results indicate that the increased level of CORT may be transient when evoked during short-term heat exposure, with regulation not dependent on AT1R. However, in an in vitro examination, AT1R activation elicited by chronic (over 24 h) and high dose (over 10 À7 M) application of Ang II was found to directly induce apoptosis of cultured hippocampal neural stem cells isolated from rats (Kim et al, 2017). Also, it has been shown that heart failure elicits AT1Rmediated cell death of newborn hippocampal neurons in rats (Kim et al, 2017).…”

Brain Renin–Angiotensin System Blockade Attenuates Methamphetamine-Induced Hyperlocomotion and Neurotoxicity

“…A recent study has proved that the effects of METH-induced neuroinflammation and neurotoxicity are attenuated through inhibition of NF-κB/STAT3/ERK and mitochondria-mediated apoptosis pathway in dopaminergic SH-SY5Y cells [65]. A previous study showed that Ang II induces apoptotic death, which is attenuated by pretreatment with Ang II receptor blockers in hippocampal neural stem cells [66]. Evidence has indicated that METH-induced apoptotic death in SH-SY5Y cell line is mediated, at least in part, through an ERdependent mechanism [67].…”