Serelaxin Treatment Reduces Oxidative Stress and Increases Aldehyde Dehydrogenase-2 to Attenuate Nitrate Tolerance

Leo, Chen Huei; Fernando, Dhanushke T; Tran, Lillie; Ng, Hooi Hooi; Marshall, Sarah A.; Parry, Laura J.

doi:10.3389/fphar.2017.00141

Cited by 21 publications

(15 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have confirmed that mitochondrial ALDH2 has the functions of reducing oxygen free radical production, scavenging aldehydes and 4-HNE, and finally protecting mitochondrial function [24, 25]. Zhang et al [26] observed that activation of ALDH2 protects rats from hepatic ischemia/reperfusion injury by inhibiting oxidative stress and clearing the accumulation of 4-HNE.…”

Section: Discussionmentioning

confidence: 99%

ALDH2 Overexpression Alleviates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation

Cao¹,

Fang²,

Wang³

et al. 2019

Journal of Diabetes Research

View full text Add to dashboard Cite

Although the underlying mechanisms of diabetes-induced myocardial injury have not been fully illuminated, the inflammation reaction has been reported intently linked with diabetes. The nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, the key component of pyroptosis, is involved in inflammation reaction, which may be one of the important mechanisms in diabetes-induced myocardial injury. The purpose of this study was to investigate the changes of NLRP3 inflammasome and pyroptosis in high glucose-induced H9C2 cardiac cell injury and investigate whether overexpression of mitochondrial aldehyde dehydrogenase 2 (ALDH2) can reduce the occurrence of pyroptosis. The H9C2 cardiac cells were exposed to 35 mM glucose for 24 h to induce cytotoxicity. Mitochondrial ALDH2 overexpression cardiac cell line was constructed. The results showed in high glucose condition that ALDH2 overexpression significantly increased H9C2 cardiac cell viability, increased mitochondrial ALDH2 activity and protein expression, and reduced mitochondrial reactive oxygen species (ROS) production, 4-hydroxynonenal (4-HNE), and lactate dehydrogenase (LDH) levels; meanwhile, the pyroptosis key components—NLRP3 inflammasome-related proteins, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cysteine-containing aspartate specific protease 1 (Caspase-1), and interleukin-18 (IL-18) protein expressions—were significantly decreased, and IL-18 and interleukin-1β (IL-1β) levels were also decreased. In high glucose-induced cardiac cell injury, ALDH2 overexpression may reduce ROS production, thereby inhibiting the activation of NLRP3 inflammation and cell pyroptosis. ALDH2 gene might play the potential role in the treatment of high glucose-induced H9C2 cardiac cell injury.

show abstract

Section: Discussionmentioning

confidence: 99%

ALDH2 Overexpression Alleviates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation

Cao¹,

Fang²,

Wang³

et al. 2019

Journal of Diabetes Research

View full text Add to dashboard Cite

show abstract

“…This suggests that relaxin may regulate eNOS function at a post‐translational level to increase NO bioavailability. We have previously shown that relaxin enhances NOS activity via reduction of vascular oxidative stress (Leo et al, ), activation of eNOS phosphorylation at Ser 1177 (Leo et al, ; Leo, Jelinic, Parkington, et al, ; McGuane et al, ), and up‐regulation of eNOS dimerisation (Jelinic et al, ). Furthermore, the ability of relaxin to increase NO bioavailability and prevent endothelial dysfunction is observed in a number of disease conditions, including TNF‐α incubation (Dschietzig et al, ), cigarette smoke (Pini et al, ), arteriosclerosis (Tiyerili et al, ), and diabetes (Ng et al, ; Ng et al, ).…”

Section: Discussionmentioning

confidence: 99%

Relaxin reduces endothelium‐derived vasoconstriction in hypertension: Revealing new therapeutic insights

Leo

Marshall

et al. 2019

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose Endothelium‐derived vasoconstriction is a hallmark of vascular dysfunction in hypertension. In some cases, an overproduction of endothelium‐derived prostacyclin (PGI2) can cause contraction rather than relaxation. Relaxin is well known for its vasoprotective actions, but the possibility that this peptide could also reverse endothelium‐derived vasoconstriction has never been investigated. We tested the hypothesis that short‐term relaxin treatment mitigates endothelium‐derived vasoconstriction in spontaneously hypertensive rats (SHR). Experimental Approach Male Wistar Kyoto rats (WKY) and SHR were subcutaneously infused with either vehicle (20 mmol·L−1 sodium acetate) or relaxin (13.3 μg·kg−1·hr−1) using osmotic minipumps for 3 days. Vascular reactivity to the endothelium‐dependent agonist ACh was assessed in vitro by wire myography. Quantitative PCR and LC‐MS were used to identify changes in gene expression of prostanoid pathways and PG production, respectively. Key Results Relaxin treatment ameliorated hypertension‐induced endothelial dysfunction by increasing NO‐dependent relaxation and reducing endothelium‐dependent contraction. Notably, short‐term relaxin treatment up‐regulated mesenteric PGI2 receptor (IP) expression, permitting PGI2–IP‐mediated vasorelaxation. In the aorta, reversal of contraction was accompanied by suppression of the hypertension‐induced increase in prostanoid‐producing enzymes and reduction in PGI2‐evoked contractions. Conclusions and Implications Relaxin has region‐dependent vasoprotective actions in hypertension. Specifically, relaxin has distinct effects on endothelium‐derived contracting factors and their associated vasoconstrictor pathways in mesenteric arteries and the aorta. Taken together, these observations reveal the potential of relaxin as a new therapeutic agent for vascular disorders that are associated with endothelium‐derived vasoconstriction including hypertension.

show abstract

“…The aortae were mounted on a wire myograph (model 610M; Danish Myo Technology, Aarhus, Denmark) as described previously [41,[58][59][60] with the following modifications. Briefly, the aorta was allowed to stabilize at zero tension for 15 min, followed by a 30 min equilibrium at 5mN.…”

Section: Assessment Of Vascular Reactivitymentioning

confidence: 99%

The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice

Marshall

Qin

Jelinic

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1/2 activation in human-engineered FPR-expressing cells, including ERK1/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.

show abstract

Serelaxin Treatment Reduces Oxidative Stress and Increases Aldehyde Dehydrogenase-2 to Attenuate Nitrate Tolerance

Cited by 21 publications

References 50 publications

ALDH2 Overexpression Alleviates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation

ALDH2 Overexpression Alleviates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation

Relaxin reduces endothelium‐derived vasoconstriction in hypertension: Revealing new therapeutic insights

The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice

Contact Info

Product

Resources

About