Research

15 pages, 4932 KiB

Open AccessArticle

The Protective Role of Glutathione against Doxorubicin-Induced Cardiotoxicity in Human Cardiac Progenitor Cells

by Eun Ji Lee, Woong Bi Jang, Jaewoo Choi, Hye Ji Lim, Sangmi Park, Vinoth Kumar Rethineswaran, Jong Seong Ha, Jisoo Yun, Young Joon Hong, Young Jin Choi and Sang-Mo Kwon

Int. J. Mol. Sci. 2023, 24(15), 12070; https://doi.org/10.3390/ijms241512070 - 28 Jul 2023

Viewed by 969

Abstract

This study investigated the protective effect of glutathione (GSH), an antioxidant drug, against doxorubicin (DOX)-induced cardiotoxicity. Human cardiac progenitor cells (hCPCs) treated with DOX (250 to 500 nM) showed increased viability and reduced ROS generation and apoptosis with GSH treatment (0.1 to 1 [...] Read more.

This study investigated the protective effect of glutathione (GSH), an antioxidant drug, against doxorubicin (DOX)-induced cardiotoxicity. Human cardiac progenitor cells (hCPCs) treated with DOX (250 to 500 nM) showed increased viability and reduced ROS generation and apoptosis with GSH treatment (0.1 to 1 mM) for 24 h. In contrast to the 500 nM DOX group, pERK levels were restored in the group co-treated with GSH and suppression of ERK signaling improved hCPCs’ survival. Similarly to the previous results, the reduced potency of hCPCs in the 100 nM DOX group, which did not affect cell viability, was ameliorated by co-treatment with GSH (0.1 to 1 mM). Furthermore, GSH was protected against DOX-induced cardiotoxicity in the in vivo model (DOX 20 mg/kg, GSH 100 mg/kg). These results suggest that GSH is a potential therapeutic strategy for DOX-induced cardiotoxicity, which performs its function via ROS reduction and pERK signal regulation. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Figure 1

15 pages, 2241 KiB

Open AccessArticle

Loss of IP3R-BK_Ca Coupling Is Involved in Vascular Remodeling in Spontaneously Hypertensive Rats

by Sayeman Islam Niloy, Yue Shen, Lirong Guo, Stephen T. O’Rourke and Chengwen Sun

Int. J. Mol. Sci. 2023, 24(13), 10903; https://doi.org/10.3390/ijms241310903 - 30 Jun 2023

Viewed by 1021

Abstract

Mechanisms by which BK_Ca (large-conductance calcium-sensitive potassium) channels are involved in vascular remodeling in hypertension are not fully understood. Vascular smooth muscle cell (VSMC) proliferation and vascular morphology were compared between hypertensive and normotensive rats. BK_Ca channel activity, protein expression, and [...] Read more.

Mechanisms by which BK_Ca (large-conductance calcium-sensitive potassium) channels are involved in vascular remodeling in hypertension are not fully understood. Vascular smooth muscle cell (VSMC) proliferation and vascular morphology were compared between hypertensive and normotensive rats. BK_Ca channel activity, protein expression, and interaction with IP3R (inositol 1,4,5-trisphosphate receptor) were examined using patch clamp, Western blot analysis, and coimmunoprecipitation. On inside-out patches of VSMCs, the Ca²⁺-sensitivity and voltage-dependence of BK_Ca channels were similar between hypertensive and normotensive rats. In whole-cell patch clamp configuration, treatment of cells with the IP3R agonist, Adenophostin A (AdA), significantly increased BK_Ca channel currents in VSMCs of both strains of rats, suggesting IP3R-BK_Ca coupling; however, the AdA-induced increases in BK_Ca currents were attenuated in VSMCs of hypertensive rats, indicating possible IP3R-BK_Ca decoupling, causing BK_Ca dysfunction. Co-immunoprecipitation and Western blot analysis demonstrated that BK_Ca and IP3R proteins were associated together in VSMCs; however, the association of BK_Ca and IP3R proteins was dramatically reduced in VSMCs of hypertensive rats. Genetic disruption of IP3R-BK_Ca coupling using junctophilin-2 shRNA dramatically augmented Ang II-induced proliferation in VSMCs of normotensive rats. Subcutaneous infusion of NS1619, a BK_Ca opener, to reverse BK_Ca dysfunction caused by IP3R-BK_Ca decoupling significantly attenuated vascular hypertrophy in hypertensive rats. In summary, the data from this study demonstrate that loss of IP3R-BK_Ca coupling in VSMCs induces BK_Ca channel dysfunction, enhances VSMC proliferation, and thus, may contribute to vascular hypertrophy in hypertension. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Figure 1

16 pages, 4990 KiB

Open AccessArticle

Dual Blockade of TGF-β Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT₁R/G_αq-Mediated TGF-β1 and ET-1 Signaling

by Ratchanee Duangrat, Warisara Parichatikanond and Supachoke Mangmool

Int. J. Mol. Sci. 2023, 24(8), 6972; https://doi.org/10.3390/ijms24086972 - 09 Apr 2023

Cited by 2 | Viewed by 1591

Abstract

Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-β1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-β1 and ET-1, and their effectors [...] Read more.

Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-β1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-β1 and ET-1, and their effectors that play an essential role in myofibroblast differentiation, are not fully understood. Therefore, we investigated the ATR networking with TGF-β1 and ET-1 and identified the signal transduction of these mediators by measuring the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen I using qRT-PCR. Myofibroblast phenotypes were monitored by α-SMA and stress fiber formation with fluorescence microscopy. Our findings suggested that Ang II induced collagen I and α-SMA synthesis and stress fiber formation through the AT₁R/G_αq axis in adult human cardiac fibroblasts (HCFs). Following AT₁R stimulation, G_αq protein, not G_βγ subunit, was required for upregulation of TGF-β1 and ET-1. Moreover, dual inhibition of TGF-β and ET-1 signaling completely inhibited Ang II-induced myofibroblast differentiation. The AT₁R/G_αq cascade transduced signals to TGF-β1, which in turn upregulated ET-1 via the Smad- and ERK1/2-dependent pathways. ET-1 consecutively bound to and activated endothelin receptor type A (ET_AR), leading to increases in collagen I and α-SMA synthesis and stress fiber formation. Remarkably, dual blockade of TGF-β receptor and ETR exhibited the restorative effects to reverse the myofibroblast phenotype induced by Ang II. Collectively, TGF-β1 and ET-1 are major effectors of AT₁R/G_αq cascade, and therefore, negative regulation of TGF-β and ET-1 signaling represents a targeted therapeutic strategy for the prevention and restoration of cardiac fibrosis. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Figure 1

26 pages, 12730 KiB

Open AccessArticle

Mechanism Repositioning Based on Integrative Pharmacology: Anti-Inflammatory Effect of Safflower in Myocardial Ischemia–Reperfusion Injury

by Feng Zhao, Hong Jiang, Tong Zhang, Hong Chen, Weijie Li, Xin Li, Ping Wang and Haiyu Xu

Int. J. Mol. Sci. 2023, 24(6), 5313; https://doi.org/10.3390/ijms24065313 - 10 Mar 2023

Cited by 3 | Viewed by 1751

Abstract

Safflower (Carthamus tinctorius. L) possesses anti-tumor, anti-thrombotic, anti-oxidative, immunoregulatory, and cardio-cerebral protective effects. It is used clinically for the treatment of cardio-cerebrovascular disease in China. This study aimed to investigate the effects and mechanisms of action of safflower extract on myocardial [...] Read more.

Safflower (Carthamus tinctorius. L) possesses anti-tumor, anti-thrombotic, anti-oxidative, immunoregulatory, and cardio-cerebral protective effects. It is used clinically for the treatment of cardio-cerebrovascular disease in China. This study aimed to investigate the effects and mechanisms of action of safflower extract on myocardial ischemia–reperfusion (MIR) injury in a left anterior descending (LAD)-ligated model based on integrative pharmacology study and ultra-performance liquid chromatography–quadrupole time-of-flight-tandem mass spectrometer (UPLC-QTOF-MS/MS). Safflower (62.5, 125, 250 mg/kg) was administered immediately before reperfusion. Triphenyl tetrazolium chloride (TTC)/Evans blue, echocardiography, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, lactate dehydrogenase (LDH) ability, and superoxide dismutase (SOD) levels were determined after 24 h of reperfusion. Chemical components were obtained using UPLC-QTOF-MS/MS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to analyze mRNA and protein levels, respectively. Safflower dose-dependently reduced myocardial infarct size, improved cardiac function, decreased LDH levels, and increased SOD levels in C57/BL6 mice. A total of 11 key components and 31 hub targets were filtered based on the network analysis. Comprehensive analysis indicated that safflower alleviated inflammatory effects by downregulating the expression of NFκB1, IL-6, IL-1β, IL-18, TNFα, and MCP-1 and upregulating NFκBia, and markedly increased the expression of phosphorylated PI3K, AKT, PKC, and ERK/2, HIF1α, VEGFA, and BCL2, and decreased the level of BAX and phosphorylated p65. Safflower shows a significant cardioprotective effect by activating multiple inflammation-related signaling pathways, including the NFκB, HIF-1α, MAPK, TNF, and PI3K/AKT signaling pathways. These findings provide valuable insights into the clinical applications of safflower. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Figure 1

14 pages, 3574 KiB

Open AccessArticle

Hydroxysafflower Yellow A Inhibits Vascular Adventitial Fibroblast Migration via NLRP3 Inflammasome Inhibition through Autophagy Activation

by Lin Liu, Qingzhuo Cui, Junna Song, Yang Yang, Yixin Zhang, Jiapeng Qi and Jingshan Zhao

Int. J. Mol. Sci. 2023, 24(1), 172; https://doi.org/10.3390/ijms24010172 - 22 Dec 2022

Cited by 1 | Viewed by 1231

Abstract

Inflammation is closely associated with progression of vascular remodeling. The NLRP3 inflammasome is the key molecule that promotes vascular remodeling via activation of vascular adventitia fibroblast (VAF) proliferation and differentiation. VAFs have a vital effect on vascular remodeling that could be improved using [...] Read more.

Inflammation is closely associated with progression of vascular remodeling. The NLRP3 inflammasome is the key molecule that promotes vascular remodeling via activation of vascular adventitia fibroblast (VAF) proliferation and differentiation. VAFs have a vital effect on vascular remodeling that could be improved using hydroxysafflower yellow A (HSYA). However, whether HSYA ameliorates vascular remodeling through inhibition of NLRP3 inflammasome activation has not been explored in detail. Here, we cultured primary VAFs and analyzed the migration of VAFs induced by angiotensin II (ANG II) to determine the potential effects and mechanism of HSYA on VAF migration. The results thereof showed that HSYA remarkably inhibited ANG II-induced VAF migration, NLRP3 inflammasome activation, and the TLR4/NF-

κ

B signaling pathway in a dose-dependent manner. In addition, it is worth noting that LPS promoted ANG II-induced VAF migration and NLRP3 inflammasome assembly, which could be significantly reversed using HSYA. Moreover, HSYA could be used to inhibit NLRP3 inflammasome activation by promoting autophagy. In conclusion, HSYA could inhibit ANG II-induced VAF migration through autophagy activation and inhibition of NLRP3 inflammasome activation through the TLR4/NF-

κ

B signaling pathway. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Figure 1

Review

Jump to: Research, Other

35 pages, 1544 KiB

Open AccessReview

New Therapeutics for Heart Failure: Focusing on cGMP Signaling

by Supachoke Mangmool, Ratchanee Duangrat, Warisara Parichatikanond and Hitoshi Kurose

Int. J. Mol. Sci. 2023, 24(16), 12866; https://doi.org/10.3390/ijms241612866 - 16 Aug 2023

Cited by 3 | Viewed by 1494

Abstract

Current drugs for treating heart failure (HF), for example, angiotensin II receptor blockers and β-blockers, possess specific target molecules involved in the regulation of the cardiac circulatory system. However, most clinically approved drugs are effective in the treatment of HF with reduced ejection [...] Read more.

Current drugs for treating heart failure (HF), for example, angiotensin II receptor blockers and β-blockers, possess specific target molecules involved in the regulation of the cardiac circulatory system. However, most clinically approved drugs are effective in the treatment of HF with reduced ejection fraction (HFrEF). Novel drug classes, including angiotensin receptor blocker/neprilysin inhibitor (ARNI), sodium-glucose co-transporter-2 (SGLT2) inhibitor, hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, soluble guanylyl cyclase (sGC) stimulator/activator, and cardiac myosin activator, have recently been introduced for HF intervention based on their proposed novel mechanisms. SGLT2 inhibitors have been shown to be effective not only for HFrEF but also for HF with preserved ejection fraction (HFpEF). In the myocardium, excess cyclic adenosine monophosphate (cAMP) stimulation has detrimental effects on HFrEF, whereas cyclic guanosine monophosphate (cGMP) signaling inhibits cAMP-mediated responses. Thus, molecules participating in cGMP signaling are promising targets of novel drugs for HF. In this review, we summarize molecular pathways of cGMP signaling and clinical trials of emerging drug classes targeting cGMP signaling in the treatment of HF. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Graphical abstract

32 pages, 1100 KiB

Open AccessReview

Therapeutic Use and Molecular Aspects of Ivabradine in Cardiac Remodeling: A Review

by Yusof Kamisah and Hamat H. Che Hassan

Int. J. Mol. Sci. 2023, 24(3), 2801; https://doi.org/10.3390/ijms24032801 - 01 Feb 2023

Cited by 7 | Viewed by 1841

Abstract

Cardiac remodeling can cause ventricular dysfunction and progress to heart failure, a cardiovascular disease that claims many lives globally. Ivabradine, a funny channel (I_f) inhibitor, is used in patients with chronic heart failure as an adjunct to other heart failure medications. [...] Read more.

Cardiac remodeling can cause ventricular dysfunction and progress to heart failure, a cardiovascular disease that claims many lives globally. Ivabradine, a funny channel (I_f) inhibitor, is used in patients with chronic heart failure as an adjunct to other heart failure medications. This review aims to gather updated information regarding the therapeutic use and mechanism of action of ivabradine in heart failure. The drug reduces elevated resting heart rate, which is linked to increased morbidity and mortality in patients with heart failure. Its use is associated with improved cardiac function, structure, and quality of life in the patients. Ivabradine exerts several pleiotropic effects, including an antiremodeling property, which are independent of its principal heart-rate-reducing effects. Its suppressive effects on cardiac remodeling have been demonstrated in animal models of cardiac remodeling and heart failure. It reduces myocardial fibrosis, apoptosis, inflammation, and oxidative stress as well as increases autophagy in the animals. It also modulates myocardial calcium homeostasis, neurohumoral systems, and energy metabolism. However, its role in improving heart failure remains unclear. Therefore, elucidating its molecular mechanisms is imperative and would aid in the design of future studies. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Figure 1

Other

Jump to: Research, Review

6 pages, 1143 KiB

Open AccessCase Report

Successful Use of Methylene Blue in Catecholamine-Resistant Septic Shock: A Case Report and Short Literature Review

by Michał P. Pluta, Zbigniew Putowski, Piotr F. Czempik and Łukasz J. Krzych

Int. J. Mol. Sci. 2023, 24(13), 10772; https://doi.org/10.3390/ijms241310772 - 28 Jun 2023

Cited by 1 | Viewed by 1460

Abstract

Despite efforts to improve treatment outcomes, mortality in septic shock remains high. In some patients, despite the use of several adrenergic drugs, features of refractory vasoplegic shock with progressive multiorgan failure are observed. We present a case report of the successful reversal of [...] Read more.

Despite efforts to improve treatment outcomes, mortality in septic shock remains high. In some patients, despite the use of several adrenergic drugs, features of refractory vasoplegic shock with progressive multiorgan failure are observed. We present a case report of the successful reversal of vasoplegic shock following the use of methylene blue, a selective inhibitor of the inducible form of nitric oxide synthase, which prevents vasodilation in response to inflammatory cytokines. We also briefly review the literature. Full article

(This article belongs to the Special Issue Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cardiovascular Pharmacology and Interventions: Future Directions for Cardioprotection 2.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Related Special Issue

Published Papers (8 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI