scholarly journals Synergetic Effect of 4-Phenylbutyric Acid in Combination with Cyclosporine A on Cardiovascular Function in Sepsis Rats via Inhibition of Endoplasmic Reticulum Stress and Mitochondrial Permeability Transition Pore Opening

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei Kuang ◽  
Yu Zhu ◽  
Yue Wu ◽  
Xiaoyong Peng ◽  
Kunlun Tian ◽  
...  
Keyword(s):  
Septic Shock ◽  
Mitochondrial Permeability Transition ◽  
Synergetic Effect ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Tissue Perfusion ◽  
Organ Injury ◽  
Therapeutic Effects ◽  
Organ Function ◽  
Phenylbutyric Acid

Background: Sepsis/septic shock is a common complication in the intensive care unit, and the opening of the mitochondrial permeability transition pore (mPTP), as well as the endoplasmic reticulum stress (ERS), play important roles in this situation. Whether the combination of anti-ERS and anti-mPTP by 4-phenylbutyric acid (PBA) and Cyclosporine A (CsA) could benefit sepsis is unclear.Methods: The cecal ligation and puncture-induced septic shock models were replicated in rats, and lipopolysaccharide (LPS)-challenged primary vascular smooth muscle cells and H9C2 cardiomyocytes in vitro models were also used. The therapeutic effects of CsA, PBA, and combined administration on oxygen delivery, cardiac and vascular function, vital organ injury, and the underlying mechanisms were observed.Results: Septic shock significantly induced cardiovascular dysfunction, hypoperfusion, and organ injury and resulted in high mortality in rats. Conventional treatment including fluid resuscitation, vasoactive agents, and antibiotics slightly restored tissue perfusion and organ function in septic rats. Supplementation of CsA or PBA improved the tissue perfusion, organ function, and survival of septic shock rats. The combined application of PBA and CsA could significantly enhance the beneficial effects, compared with using PBA or CsA alone. Further study showed that PBA enhanced CsA-induced cardiovascular protection, which contributed to better therapeutic effects.Conclusion: Anti-ERS and anti-mPTP-opening by the combination of PBA and CsA was beneficial to septic shock. PBA enforced the CsA-associated cardiovascular protection and contributed to the synergetic effect.

scholarly journals Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury

2021 ◽  
Author(s):  
Gentaro Ikeda ◽  
Tetsuya Matoba ◽  
Ayako Ishikita ◽  
Kazuhiro Nagaoka ◽  
Kaku Nakano ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Therapeutic Effects ◽  
Mitochondrial Permeability ◽  
Permeability Transition Pore Opening ◽  
Myocardial Ischemia Reperfusion

Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia‐reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle‐mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C‐C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30–45 minutes) after reperfusion, whereas C‐C chemokine receptor 2 contributes to IR injury at later time point (45–60 minutes) after reperfusion. Double deficiency of CypD and C‐C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C‐C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly‐6C high monocytes after myocardial IR injury. In CypD‐knockout mice, administration of interleukin‐1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly‐lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte‐mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle‐mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.

Cardioprotective and Vasoprotective Effects of Corticotropin-Releasing Hormone and Urocortins: Receptors and Signaling

2021 ◽  
pp. 107424842098530
Author(s):  
Sergey V. Popov ◽  
Ekaterina S. Prokudina ◽  
Alexander V. Mukhomedzyanov ◽  
Natalia V. Naryzhnaya ◽  
Huijie Ma ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Vascular Endothelial Cells ◽  
Isolated Heart ◽  
Cardiac Contractility ◽  
Permeability Transition Pore ◽  
Chronic Administration ◽  
Permeability Transition ◽  
Janus Kinase ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone

Despite the recent progress in research and therapy, cardiovascular diseases are still the most common cause of death worldwide, thus new approaches are still needed. The aim of this review is to highlight the cardioprotective potential of urocortins and corticotropin-releasing hormone (CRH) and their signaling. It has been documented that urocortins and CRH reduce ischemic and reperfusion (I/R) injury, prevent reperfusion ventricular tachycardia and fibrillation, and improve cardiac contractility during reperfusion. Urocortin-induced increase in cardiac tolerance to I/R depends mainly on the activation of corticotropin-releasing hormone receptor-2 (CRHR2) and its downstream pathways including tyrosine kinase Src, protein kinase A and C (PKA, PKCε) and extracellular signal-regulated kinase (ERK1/2). It was discussed the possibility of the involvement of interleukin-6, Janus kinase-2 and signal transducer and activator of transcription 3 (STAT3) and microRNAs in the cardioprotective effect of urocortins. Additionally, phospholipase-A2 inhibition, mitochondrial permeability transition pore (MPT-pore) blockade and suppression of apoptosis are involved in urocortin-elicited cardioprotection. Chronic administration of urocortin-2 prevents the development of postinfarction cardiac remodeling. Urocortin possesses vasoprotective and vasodilator effect; the former is mediated by PKC activation and prevents an impairment of endothelium-dependent coronary vasodilation after I/R in the isolated heart, while the latter includes both cAMP and cGMP signaling and its downstream targets. As CRHR2 is expressed by both cardiomyocytes and vascular endothelial cells. Urocortins mediate both endothelium-dependent and -independent relaxation of coronary arteries.

Sign in / Sign up

Export Citation Format

Share Document