Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy

Mathari, Brahim El; Briand, Pascale; Corbier, Alain; Poirier, Bruno; Briand, Véronique; Raffenne-Devillers, Alice; Harnist, Marie-Pierre; Guillot, Etienne; Guilbert, F; Janiak, Philip

doi:10.1016/j.peptides.2021.170568

“…Another significant network strictly linked from a functional perspective with both NOS2 and EP300 was ascribable to the Apelin signalling pathway (Supplement table 3). Activation of the Apelin-receptor system was shown to induce vessel relaxation and cardiac contractility in rodents, both in vivo and in isolated heart models, through the production and release of NO (Zhong et al, 2007 ;Trân et al, 2018 ;Mathari et al, 2021). The complex functional connections between EP300/NOS2 and genes playing a role in such processes thus provide additional evidence supporting their potential adaptive role in high-altitude Tibetan and Sherpa populations.…”

Section: Discussionmentioning

confidence: 97%

“…In line with what emerged from STRING enrichment analysis, many significant gene networks pointed out by the Signet algorithm were found to be involved in the same biological functions to which the core set of candidate genes identified by VolcanoFinder contributes (e.g., promotion of angiogenesis and induction of nitric oxide, NO) (Figure 3 , Supplement Table 3). For instance, some significant gene networks were found to belong to the JAK-STAT signalling, PI3K-Akt signalling, Apelin signalling and VEGF signalling pathways that are known to be connected with each other and to be activated in hypoxic conditions to induce transcription of genes related with angiogenesis (Kanehisa et al, 2000, Fresno Vara et al, 2004Ashley et al, 2005;Trân et al, 2018 ;Johnson et al, 2018;Mathari et al, 2021;Sahinturk et al, 2021) (Supplement Table 3). These signalling cascades determinate also the expression of EP300 and NOS2 genes and are capable to modulate tumour invasiveness, metastasis, and induction of NO (Kanehisa et al, 2000 ;Wang et al, 2005;Zhang et al, 2011;Johnson et al, 2018).…”

Section: Detecting Adaptive Introgression Signatures Across Functiona...mentioning

confidence: 99%

Archaic introgression contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in human high-altitude populations from the Himalayas

Ferraretti,

Abondio,

Alberti

et al. 2023

Preprint

0

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It is well established that several Homo sapiens populations experienced admixture with extinct human species during their evolutionary history. Sometimes, such a gene flow could have played a role in modulating their capability to cope with a variety of selective pressures, thus resulting in archaic adaptive introgression events. A paradigmatic example of this evolutionary mechanism is offered by the EPAS1 gene, whose most frequent haplotype in Himalayan highlanders was proved to reduce their susceptibility to chronic mountain sickness and to be introduced in the gene pool of their ancestors by admixture with Denisovans. In this study, we aimed at further expanding the investigation of the impact of archaic introgression on more complex adaptive responses to hypobaric hypoxia evolved by populations of Tibetan and Sherpa ancestry, which have been plausibly mediated by soft selective sweeps and/or polygenic adaptations rather than by hard selective sweeps. For this purpose, we used a combination of composite-likelihood and gene network-based methods to detect adaptive loci in introgressed chromosomal segments from Tibetan whole genome sequence data and to shortlist those enriched for Denisovan-like derived alleles that participate to the same functional pathways. According to this approach, we identified multiple genes putatively involved in archaic introgression events and that, especially as regards EP300 and NOS2, have plausibly contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in high-altitude Himalayan peoples. These findings provided unprecedented evidence about the complexity of the adaptive phenotype evolved by these human groups to cope with challenges imposed by hypobaric hypoxia, offering new insights into the tangled interplay of genetic determinants that mediates the physiological adjustments crucial for human adaptation to the high-altitude environment.

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“…Another significant network strictly linked from a functional perspective with both NOS2 and EP300 was ascribable to the Apelin signalling pathway (Supplement table 3). Activation of the Apelin-receptor system was shown to induce vessel relaxation and cardiac contractility in rodents, both in vivo and in isolated heart models, through the production and release of NO (Zhong et al, 2007 ;Trân et al, 2018 ;Mathari et al, 2021). The complex functional connections between EP300/NOS2 and genes playing a role in such processes thus provide additional evidence supporting their potential adaptive role in high-altitude Tibetan and Sherpa populations.…”

Section: Discussionmentioning

confidence: 97%

“…In line with what emerged from STRING enrichment analysis, many significant gene networks pointed out by the Signet algorithm were found to be involved in the same biological functions to which the core set of candidate genes identified by VolcanoFinder contributes (e.g., promotion of angiogenesis and induction of nitric oxide, NO) (Figure 3 , Supplement Table 3). For instance, some significant gene networks were found to belong to the JAK-STAT signalling, PI3K-Akt signalling, Apelin signalling and VEGF signalling pathways that are known to be connected with each other and to be activated in hypoxic conditions to induce transcription of genes related with angiogenesis (Kanehisa et al, 2000, Fresno Vara et al, 2004Ashley et al, 2005;Trân et al, 2018 ;Johnson et al, 2018;Mathari et al, 2021;Sahinturk et al, 2021) (Supplement Table 3). These signalling cascades determinate also the expression of EP300 and NOS2 genes and are capable to modulate tumour invasiveness, metastasis, and induction of NO (Kanehisa et al, 2000 ;Wang et al, 2005;Zhang et al, 2011;Johnson et al, 2018).…”

Section: Detecting Adaptive Introgression Signatures Across Functiona...mentioning

confidence: 99%

Archaic introgression contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in human high-altitude populations from the Himalayas

Ferraretti,

Abondio,

Alberti

et al. 2023

Preprint

0

View full text Add to dashboard Cite

It is well established that several Homo sapiens populations experienced admixture with extinct human species during their evolutionary history. Sometimes, such a gene flow could have played a role in modulating their capability to cope with a variety of selective pressures, thus resulting in archaic adaptive introgression events. A paradigmatic example of this evolutionary mechanism is offered by the EPAS1 gene, whose most frequent haplotype in Himalayan highlanders was proved to reduce their susceptibility to chronic mountain sickness and to be introduced in the gene pool of their ancestors by admixture with Denisovans. In this study, we aimed at further expanding the investigation of the impact of archaic introgression on more complex adaptive responses to hypobaric hypoxia evolved by populations of Tibetan and Sherpa ancestry, which have been plausibly mediated by soft selective sweeps and/or polygenic adaptations rather than by hard selective sweeps. For this purpose, we used a combination of composite-likelihood and gene network-based methods to detect adaptive loci in introgressed chromosomal segments from Tibetan whole genome sequence data and to shortlist those enriched for Denisovan-like derived alleles that participate to the same functional pathways. According to this approach, we identified multiple genes putatively involved in archaic introgression events and that, especially as regards EP300 and NOS2, have plausibly contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in high-altitude Himalayan peoples. These findings provided unprecedented evidence about the complexity of the adaptive phenotype evolved by these human groups to cope with challenges imposed by hypobaric hypoxia, offering new insights into the tangled interplay of genetic determinants that mediates the physiological adjustments crucial for human adaptation to the high-altitude environment.

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“…Under pathological conditions, accumulating evidence suggests that the apelin/APLNR system has multiple roles ( Lu et al, 2017 ; de Oliveira et al, 2022 ). In terms of beneficial effects, apelin improved cardiac function in mice with post-myocardial infarction heart failure dilated cardiomyopathy ( Berry et al, 2004 ; El Mathari et al, 2021 ). Furthermore, apelin also reduced blood pressure in DOCA salt-induced hypertensive rats ( Akcılar et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Apelin receptor inhibition in ischemia-reperfused mouse hearts protected by endogenous n-3 polyunsaturated fatty acids

Zheng,

Tan,

Li

et al. 2023

Front. Pharmacol.

0

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Background: While the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on cardiac ischemia-reperfusion (IR) injury have been previously reported, limited data are available regarding how these fatty acids affect membrane receptors and their downstream signaling following IR injury. We aimed to identify potential receptors activated by n-3 PUFAs in IR hearts to understand the regulatory mechanisms of these receptors.Methods: We used fat-1 mice, which naturally have elevated levels of n-3 PUFAs, and C57BL/6J mice as a control group to create a myocardial IR injury model through Langendorff perfusion. We assessed the impact of endogenous n-3 PUFAs on left ventricular function, myocardial infarct size, myocardial apoptosis, and ATP production. RNA sequencing (RNA-seq) and bioinformatics analysis were conducted to identify molecular targets affected by n-3 PUFAs. Based on these analyses we then treated IR hearts of WT and fat-1 mice with an antagonist (ML221) or an agonist (apelin-13) for the predicted receptor to assess cardiac contractile function and intracellular signaling pathways. An in vitro hypoxia-reoxygenation (HR) model was also used to confirm the effects of n-3 PUFAs on the examined intracellular signaling pathways.Results: Endogenous n-3 PUFAs protected cardiac structure and function in post-IR hearts, and modulated phosphorylation patterns in the PI3K-AKT-mTOR signaling pathways. RNA-seq analysis revealed that n-3 PUFAs affected multiple biological processes as well as levels of the apelin receptor (APLNR). Consistent with a role for the PLNNR, ML221 synchronized the activation of the PI3K-AKT-mTOR signaling axis, suppressed the expression of PKCδ and phosphorylated p38α, upregulated PKCε expression, upregulated or restored the phosphorylation of myofilaments, and prevented myocardial injury and contractile dysfunction in WT IR hearts. By contrast, apelin-13 disrupted the PI3K-AKT-mTOR signaling axis in post-IR fat-1 hearts. The phosphorylation signaling targeted by APLNR inhibition in post-IR fat-1 hearts was also observed after treating HR cells with eicosatetraenoic acid (EPA).Conclusion: Endogenous n-3 PUFAs protect against post-IR injury and preserve cardiac contractile function possibly through APLNR inhibition. This inhibition synchronizes the PI3K-AKT-mTOR axis, suppresses detrimental phosphorylation signaling, and restores or increases myofilament phosphorylation in post-IR hearts. The beneficial effects observed in fat-1 transgenic mouse hearts can be attributed, at least in part, to elevated EPA levels. This study is the first to demonstrate that n-3 PUFAs protect hearts against IR injury through APLNR inhibition.

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Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy

Cited by 9 publications

References 39 publications

Archaic introgression contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in human high-altitude populations from the Himalayas

Archaic introgression contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in human high-altitude populations from the Himalayas

Archaic introgression contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in human high-altitude populations from the Himalayas

Apelin receptor inhibition in ischemia-reperfused mouse hearts protected by endogenous n-3 polyunsaturated fatty acids

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