Role of the <scp>MPTP</scp> in conditioning the heart – translatability and mechanism

Ong, Sang-Ging; Dongworth, Rachel K; Cabrera-Fuentes, Héctor A.; Hausenloy, Derek J.

doi:10.1111/bph.13013

Cited by 65 publications

(61 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Critical target of IPC is the mPTP whose excessive opening in the first few minutes of reperfusion induces cardiomyocyte death. Key inducers of mPTP opening are ATP depletion, excessive generation of ROS, mitochondrial Ca 2+ overload and changes of intracellular pH 32 . Therefore, preserving ATP levels, attenuation of oxidative stress and mitochondrial Ca 2+ overload, and delayed correction of ischemia-induced intracellular acidosis are integrated in the IPC-mediated inhibition of mPTP opening 33,34 .…”

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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Although the mechanisms underlying ischemic post-conditioning are not fully elucidated, it has been shown to be associated with inhibition of mPTP opening. This may be partially explained by maintenance of an acid pH (inhibitory for mPTP opening) for longer during the early stages of reperfusion, but other signalling pathways are also thought to be involved [44,55]. There are no published data to show that reduced ROS production during the early stages of reperfusion post-conditioning is the mechanism by which it inhibits mPTP.…”

Section: Discussionmentioning

confidence: 99%

Real-Time Fluorescence Measurements of ROS and [Ca2+] in Ischemic / Reperfused Rat Hearts: Detectable Increases Occur only after Mitochondrial Pore Opening and Are Attenuated by Ischemic Preconditioning

et al. 2016

View full text Add to dashboard Cite

Mitochondrial permeability transition pore (mPTP) opening is critical for ischemia / reperfusion (I/R) injury and is associated with increased [Ca2+] and reactive oxygen species (ROS). Here we employ surface fluorescence to establish the temporal sequence of these events in beating perfused hearts subject to global I/R. A bespoke fluorimeter was used to synchronously monitor surface fluorescence and reflectance of Langendorff-perfused rat hearts at multiple wavelengths, with simultaneous measurements of hemodynamic function. Potential interference by motion artefacts and internal filtering was assessed and minimised. Re-oxidation of NAD(P)H and flavoproteins on reperfusion (detected using autofluorescence) was rapid (t0.5 < 15 s) and significantly slower following ischemic preconditioning (IP). This argues against superoxide production from reduced Complex 1 being a critical mediator of initial mPTP opening during early reperfusion. Furthermore, MitoPY1 (a mitochondria-targeted H2O2-sensitive fluorescent probe) and aconitase activity measurements failed to detect matrix ROS increases during early reperfusion. However, two different fluorescent cytosolic ROS probes did detect ROS increases after 2–3 min of reperfusion, which was shown to be after initiation of mPTP opening. Cyclosporin A (CsA) and IP attenuated these responses and reduced infarct size. [Ca2+]i (monitored with Indo-1) increased progressively during ischemia, but dropped rapidly within 90 s of reperfusion when total mitochondrial [Ca2+] was shown to be increased. These early changes in [Ca2+] were not attenuated by IP, but substantial [Ca2+] increases were observed after 2–3 min reperfusion and these were prevented by both IP and CsA. Our data suggest that the major increases in ROS and [Ca2+] detected later in reperfusion are secondary to mPTP opening. If earlier IP-sensitive changes occur that might trigger initial mPTP opening they are below our limit of detection. Rather, we suggest that IP may inhibit initial mPTP opening by alternative mechanisms such as prevention of hexokinase 2 dissociation from mitochondria during ischemia.

show abstract

“…For example, evidence shows that PKG can protect cells from IR injury by activating signaling cascades that delay mPTP opening [60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

Riquelme

Westermeier

Hall

et al. 2016

Pharmacological Research

View full text Add to dashboard Cite

show abstract

Role of the MPTP in conditioning the heart – translatability and mechanism

Cited by 65 publications

References 131 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

Real-Time Fluorescence Measurements of ROS and [Ca2+] in Ischemic / Reperfused Rat Hearts: Detectable Increases Occur only after Mitochondrial Pore Opening and Are Attenuated by Ischemic Preconditioning

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

Contact Info

Product

Resources

About