Mitochondrial angiotensin receptors and cardioprotective pathways

Escobales, Nelson; Nuñez, Rebeca E.; Javadov, Sabzali

doi:10.1152/ajpheart.00772.2018

Cited by 38 publications

(32 citation statements)

References 108 publications

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“…Although it was not the intention of the present study to unravel the mechanism of action, some speculations may be allowed here. First of all, cytosolic renin may contribute to angiotensin generation within the cytosol or even within mitochondria, although this matter is discussed controvers (for review see: [36][37][38] ). Data from diabetic animals and patients demonstrate an increased intracellular ANG II level which is associated with enhanced oxidative stress, fibrosis, and cardiac cell apoptosis and necrosis 39 .…”

Section: Discussionmentioning

confidence: 99%

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Wanka

Lutze

Staar

et al. 2020

Sci Rep

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Although the renin-angiotensin system usually promotes oxidative stress and cell death, renin transcripts have been discovered, whose transcription product may be cardioprotective. these transcripts encode a non-secretory renin isoform that is localized in the cytosol and within mitochondria. Here we tested the hypotheses that cytosolic renin [ren(2-9)] expression promotes cell survival under hypoxia and glucose depletion by preserving the mitochondrial membrane potential (∆Ψ m ) and mitigating the accumulation of ROS. To simulate ischemic insults, we exposed H9c2 cells to glucose deprivation, anoxia or to combined oxygen-glucose deprivation (OGD) for 24 hours and determined renin expression. Furthermore, H9c2 cells transfected with the empty pIRES vector (pIRES cells) or ren(2-9) cDNA-containing vector [ren(2-9) cells] were analyzed for cell death, ∆Ψ m , Atp levels, accumulation of RoS, and cytosolic ca 2+ content. In pIRES cells, expression of ren(1A-9) was stimulated under all three ischemia-related conditions. After oGD, the cells lost their ∆Ψ m and exhibited enhanced RoS accumulation, increased cytosolic ca 2+ levels, decreased Atp levels as well as increased cell death. In contrast, ren(2-9) cells were markedly protected from these effects. Ren(2-9) appears to represent a protective response to oGD by reducing RoS generation and preserving mitochondrial functions. therefore, it is a promising new target for the prevention of ischemia-induced myocardial damage.Myocardial infarction is a major cause of death worldwide. Given the high incidence of myocardial infarction and the associated cardiac injury, developing novel strategies and countermeasures to protect the heart against acute and especially ischemia/reperfusion-induced damage is of great interest.Renin is known as secretory glycoprotein that generates angiotensin (ANG) I from angiotensinogen. ANG I is further cleaved to ANG II by the angiotensin-converting enzyme. ANG II increases blood pressure as well as salt-and water reabsorption. Furthermore, ANG II enhances oxidative stress, exerts pro-inflammatory effects and induces apoptotic and necrotic cell death, particularly in the heart and the kidney. Correspondingly, inhibitors of the renin-angiotensin system (RAS) are among the most potent drugs in the treatment of hypertension and cardiac failure, markedly increasing the life span of patients 1 .Alternative renin transcripts, termed exon1A renin, exon(2-9)renin, renin-b or renin-c, have been identified in rats and mice 2,3 as well as in transgenic mice expressing a human renin gene construct 4 . In the rat heart, exon(1A-9) renin transcription is under the control of an alternative promoter located in intron 1 5 . In cardiac cells, this promoter is stimulated by glucose depletion in a serum response factor-dependent manner 5 . Furthermore, exon(1A-9) renin mRNA abundance increased markedly after myocardial infarction in vivo 6 . Due to the absence of the signal for a co-translational transport to the endoplasmatic reticulum, encoded by exon1, all a...

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Section: Discussionmentioning

confidence: 99%

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Wanka

Lutze

Staar

et al. 2020

Sci Rep

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“…The initiation of ACE2-dependent endocytosis in SARS-CoV-2 was reported to be dependent on phosphatidylinositole biphosphate (Ou et al, 2020). The protease-independent and lipid-raft-mediated entry might mimic physiological activation of the receptor by angiotensin II, which results in its recruitment to the intracellular renin-angiotensin system (Escobales et al, 2019;Abassi et al, 2020). We still do not know much of this system, nonetheless, its involvement in the various aspects of metabolic regulation of subcellular compartments is gradually being elucidated (Villar-Cheda et al, 2017;Shi et al, 2018;Sotomayor-Flores et al, 2020).…”

Section: Internalization Of Ace2 As a Dominant Entry Mechanismmentioning

confidence: 99%

SARS-CoV-2 Dissemination Through Peripheral Nerves Explains Multiple Organ Injury

Fenrich

Mrđenović

Balog

et al. 2020

Front. Cell. Neurosci.

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Coronavirus disease (CoVID-19), caused by recently identified severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2), is characterized by inconsistent clinical presentations. While many infected individuals remain asymptomatic or show mild respiratory symptoms, others develop severe pneumonia or even respiratory distress syndrome. SARS-CoV-2 is reported to be able to infect the lungs, the intestines, blood vessels, the bile ducts, the conjunctiva, macrophages, T lymphocytes, the heart, liver, kidneys, and brain. More than a third of cases displayed neurological involvement, and many severely ill patients developed multiple organ infection and injury. However, less than 1% of patients had a detectable level of SARS-CoV-2 in the blood, raising a question of how the virus spreads throughout the body. We propose that nerve terminals in the orofacial mucosa, eyes, and olfactory neuroepithelium act as entry points for the brain invasion, allowing SARS-CoV-2 to infect the brainstem. By exploiting the subcellular membrane compartments of infected cells, a feature common to all coronaviruses, SARS-CoV-2 is capable to disseminate from the brain to periphery via vesicular axonal transport and passive diffusion through axonal endoplasmic reticula, causing multiple organ injury independently of an underlying respiratory infection. The proposed model clarifies a wide range of clinically observed phenomena in CoVID-19 patients, such as neurological symptoms unassociated with lung pathology, protracted presence of the virus in samples obtained from recovered patients, exaggerated immune response, and multiple organ failure in severe cases with variable course and dynamics of the disease. We believe that this model can provide novel insights into CoVID-19 and its long-term sequelae, and establish a framework for further research.

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“…In particular, augmented Bk levels mediate protection against MIRI at myocardial [125][126][127] end endothelial level [129], whereas AT1Rs blocking inhibits pro-apoptotic pathways mediated by acute Ang II increase. Consistently, the reflex increased Ang II levels may activate cRAS and iRAS that enhance cell protection against oxidative stress [115]. Furthermore, SAC/VAL may prevent the long-term harmful accumulation of SP, because this peptide is broken down by the uninhibited ACE, thereby exploiting acute SP positive effects on MIRI prevention [169][170][171].…”

Section: Clinical Perspectives For Nep Inhibition In Miri Preventionmentioning

confidence: 93%

“…Notably, the intracellular RAS (iRAS) described in neurons, fibroblasts, renal cells, and cardiomyocytes provided new insights into regulatory mechanisms mediated by intracellular Ang II type 1 (AT1Rs) and 2 (AT2Rs) receptors, particularly in mitochondria and nucleus. For instance, Ang II, through nuclear AT1Rs, promotes protective mechanisms through the stimulation of AT2R signaling cascade, which involves mitochondrial AT2Rs and Mas receptors [115]. The stimulation of nuclear Ang II receptors enhances mitochondrial biogenesis by peroxisome proliferator-activated receptor-γ coactivator-1α and increases sirtuins activity, thereby protecting the cell against oxidative stress [115].…”

Section: Angiotensin (Ang)mentioning

confidence: 99%

“…For instance, Ang II, through nuclear AT1Rs, promotes protective mechanisms through the stimulation of AT2R signaling cascade, which involves mitochondrial AT2Rs and Mas receptors [115]. The stimulation of nuclear Ang II receptors enhances mitochondrial biogenesis by peroxisome proliferator-activated receptor-γ coactivator-1α and increases sirtuins activity, thereby protecting the cell against oxidative stress [115]. Thus, despite abundant data on the deleterious effects of Ang II, a growing body of studies also supports a protective role for cRAS and iRAS that could be of relevance to support the hypothesis of NEP inhibition in MIRI prevention.…”

Section: Angiotensin (Ang)mentioning

confidence: 99%

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The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction

Bellis¹,

Mauro

Barbato³

et al. 2020

Cells

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During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a “multi-targeted cardioprotective therapy”, defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.

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Mitochondrial angiotensin receptors and cardioprotective pathways

Cited by 38 publications

References 108 publications

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

SARS-CoV-2 Dissemination Through Peripheral Nerves Explains Multiple Organ Injury

The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction

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