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Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.

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IntroductionQuercetin (Que) is a potent anti-inflammatory and antioxidant flavonoid with cardioprotective potential. However, very little is known about the signaling pathways and gene regulatory proteins Que may interfere with, especially in diabetic cardiomyopathy. Therefore, we aimed to study the potential cardioprotective effects of Que on the cardiac phenotype of type 2 diabetes mellitus (T2DM) accompanied by obesity.MethodsFor this experiment, we used Zucker Diabetic Fatty rats (fa/fa) and their age-matched lean controls (fa/+) that were treated with either vehicle or 20 mg/kg/day of Que for 6 weeks. Animals underwent echocardiographic (echo) examination before the first administration of Que and after 6 weeks. ResultsAfter the initial echo examination, the diabetic rats showed increased E/A ratio, a marker of left ventricular (LV) diastolic dysfunction, in comparison to the control group which was selectively reversed by Que. Following the echo analysis, Que reduced LV wall thickness and exhibited an opposite effect on LV luminal area. In support of these results, the total collagen content measured by hydroxyproline assay was decreased in the LVs of diabetic rats treated with Que. The follow-up immunoblot analysis of proteins conveying cardiac remodeling pathways revealed that Que was able to interfere with cardiac pro-hypertrophic signaling. In fact, Que reduced relative protein expression of pro-hypertrophic transcriptional factor MEF2 and its counter-regulator HDAC4 along with pSer246-HDAC4. Furthermore, Que showed potency to decrease GATA4 transcription factor, NFAT3 and calcineurin, as well as upstream extracellular signal-regulated kinase Erk5 which orchestrates several pro-hypertrophic pathways.DiscussionIn summary, we showed for the first time that Que ameliorated pro-hypertrophic signaling on the level of epigenetic regulation and targeted specific upstream pathways which provoked inhibition of pro-hypertrophic signals in ZDF rats. Moreover, Que mitigated T2DM and obesity-induced diastolic dysfunction, therefore, might represent an interesting target for future research on novel cardioprotective agents.

Diabetes mellitus is known to produce various cell-damaging events and thereby underlie heart dysfunction and remodeling. However, very little is known about its inflammation-associated pathomechanisms due to necrosis-like cell death. For this purpose, we aimed to investigate signaling pathways of necroptosis and pyroptosis, known to produce plasma membrane rupture with the resultant promotion of inflammation. One-year old Zucker diabetic fatty (ZDF) rats did not exhibit significant heart dysfunction as revealed by echocardiographic measurement. On the other hand, there was a decrease in heart rate due to diabetes. Immunoblotting analysis showed that the left ventricles of ZDF rats overexpress neither the main necroptotic proteins including receptor-interacting protein kinase 3 (RIP3) and mixed lineage domain kinase-like pseudokinase (MLKL), nor the pyroptotic regulators including NLR family pyrin domain containing 3 protein (NLRP3), caspase-1, interleukin-1 beta (IL-1β and the N-terminal gasdermin D (GSDMD-N). On the other hand, the increased activation of the RIP3 kinase due to phosphorylation was found in such hearts. In summary, we showed for the first time that the activation of cardiac RIP3 is upregulated due to disturbances in glucose metabolism which, however, did not proceed to necrosis-like cell death. These data can indicate that the activated RIP3 might also underlie other pleiotropic, non-necroptotic signaling pathways under basal conditions.