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    • Given that the FST protocol

    2023-02-06

    Given that the FST protocol for mice does not engage the exposure to a previous stressful session, posits that Agtr1a levels could be kept higher by basal glutamatergic transmission rather than by stressful stimuli as postulated before. To address this possibility, we used the EMBL-EBI Expression Atlas (https://www.ebi.ac.uk/gxa/home) to compare the expression of Agtr1a and Agtr2 in the murine brain. We only obtained data from RNAseq experiments conducted in four strains of mice by Gregg and colleagues (Gregg et al., 2010). Consistent with the proposed scenario, these authors observed that Agtr2 levels were lower or at least equivalent to Agtr1a in the medial prefrontal cortex of adult mice. Our behavioral data, indicating the effectiveness of losartan in mice submitted to FST, also suggests that the Agtr1a/2 ratio in vivo favors Agtr1a, since no previous stressful event is presented in this protocol. The data obtained from mouse FST, indicating that animals lacking one copy of BDNF gene do not respond to losartan, is also apparently contradicting the in vitro lack of interaction between TRKB.Fc and ANG2. However, the differences between the systems used can be crucial to the observed responses. As mentioned, in adult prefrontal cortex, the levels of Agtr1a are higher than Agtr2, while we observed the opposite in the cultivated cells. Another source of variation relies on the fact that cultivated 8380 are not part of an intrincated, fine-tuned network, therefore submitted to less influence of the neighboring cells or structures. Supporting our in vivo findings, the decrease of BDNF levels in rats through the injection of shRNA, blocked the neuroprotective effects of candesartan in a model of stroke (Fouda et al., 2017). The activation of AGTR1 increases BDNF expression, as found in human and rat adrenocortical cells (Szekeres et al., 2010), an effect shared by AGTR2 (Alhusban et al., 2013; Namsolleck et al., 2013), and associated to the improvement in cognitive performance after telmisartan (Kishi et al., 2012). Thus, in a speculative scenario, there is a positive feedback on BDNF production by both receptors. However, the AGTR2/TRKB heterodimer is positioned in the membrane; given that the majority of TRKB is internalized (Haapasalo et al., 2002); where it can be activated by BDNF. Such effect of BDNF would then be enhanced by the recruitment of FYN or other SRC-family kinases by the activation of AGTR2.
    Funding and disclosure This work was supported by CNPq and FAPESP (for experiments conducted in Brazil) and by ERC #322742 (for experiments conducted in Finland). The authors declare no conflict of interest.
    Acknowledgments
    Introduction The publication in 1987 of the Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) heralded the beginning of 30 years of landmark randomised controlled trials (RCT) demonstrating the benefits of neurohumoral antagonists such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA) and beta-blockers in reducing the morbidity and mortality from heart failure with reduced ejection fraction (HFrEF) [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]]. Additional benefits in specific patients have also been demonstrated with implantable cardioverter defibrillators (ICD), cardiac resynchronisation therapy (CRT) and ivabradine, an inhibitor of the sinus node I current [[12], [13], [14], [15], [16], [17], [18]]. Despite this substantial progress, significant challenges remain, with an increasingly elderly population and the improvements in the survival from myocardial infarction thought to contribute to a rising prevalence of HFrEF [19]. Sacubitril/valsartan (previously known as LCZ696), a combined angiotensin receptor-neprilysin inhibitor (ARNI), represents a significant breakthrough in the management of HFrEF. The results of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial were the first to demonstrate efficacy of a new class of medication over the gold-standard ACE inhibitor enalapril, in reducing mortality, risk of HF hospitalisation and symptoms in patients with chronic, symptomatic, ambulatory HFrEF [20]. This article will review the development of sacubitril/valsartan, the evidence for its use and its current and potential future role in the management of HFrEF.