Angiotensin 1 Peptide-conjugated CdSe/ZnS Quantum Dots for Cardiac-specific Hydrogen Sulfide Targeted Therapy in Myocardial Ischemia-reperfusion Injury

Overview

Journal Front Pharmacol

Date 2024 Oct 17

PMID 39415837

Authors

Qing Wang

Xiaofei Xue

Pei Wang

Yue Yu

Jun Wang

Qixia Jiang

Jian Xiao

Affiliations

Soon will be listed here.

Abstract

Introduction: Myocardial ischemia/reperfusion (I/R) injury remains a major obstacle in cardiovascular therapies. Hydrogen sulfide (HS) shows promise for mitigating I/R injury, but conventional delivery methods, such as NaHS injections or adenovirus-mediated CSE gene therapy, face low efficiency and systemic side effects. This study explores the use of angiotensin 1 (AT1) peptide-conjugated CdSe/ZnS quantum dots (QDs) for targeted delivery of cystathionine-γ-lyase (CSE) plasmids to the myocardium, aiming to boost local HS production and minimize I/R injury.

Methods: CdSe/ZnS QDs were conjugated with AT1 peptides to create a nanocarrier system capable of delivering the CSE plasmid specifically to the myocardium. fluorescence imaging confirmed heart-specific accumulation. Myocardial infarct size, cardiac function, cell death, and oxidative stress were evaluated. Endoplasmic reticulum stress and mitophagy markers, including CHOP/GRP78/eIF2α, were analyzed, and the gene's role was further assessed using an adenovirus vector.

Results: The AT1-conjugated nanocarriers significantly increased CSE expression in the myocardium, as confirmed by fluorescence imaging, without affecting other organs. This localized delivery reduced myocardial infarct size, improved cardiac function, and decreased oxidative stress and cell death. Importantly, a reduction in endoplasmic reticulum stress and mitophagy markers was observed, suggesting that cardioprotection was mediated via the CHOP/GRP78/eIF2α signaling pathway. Reintroduction of using an adenovirus vector reversed these protective effects, confirming the pathway's involvement.

Discussion: This study demonstrates that AT1 peptide-conjugated QDs can effectively deliver CSE plasmids to the heart, providing significant protection against I/R injury through enhanced localized HS production. This approach offers a promising, targeted, and side-effect-free therapy for myocardial I/R injury, with potential for clinical translation.

References

Shen Y, Shen Z, Luo S, Guo W, Zhu Y . The Cardioprotective Effects of Hydrogen Sulfide in Heart Diseases: From Molecular Mechanisms to Therapeutic Potential. Oxid Med Cell Longev. 2015; 2015:925167. PMC: 4442295. DOI: 10.1155/2015/925167. View

Xiao J, Zhu X, Kang B, Xu J, Wu L, Hong J . Hydrogen Sulfide Attenuates Myocardial Hypoxia-Reoxygenation Injury by Inhibiting Autophagy via mTOR Activation. Cell Physiol Biochem. 2015; 37(6):2444-53. DOI: 10.1159/000438597. View

Elrod J, Calvert J, Morrison J, Doeller J, Kraus D, Tao L . Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci U S A. 2007; 104(39):15560-5. PMC: 2000503. DOI: 10.1073/pnas.0705891104. View

Ford W, Clanachan A, Jugdutt B . Opposite effects of angiotensin AT1 and AT2 receptor antagonists on recovery of mechanical function after ischemia-reperfusion in isolated working rat hearts. Circulation. 1996; 94(12):3087-9. DOI: 10.1161/01.cir.94.12.3087. View

Karwi Q, Bice J, Baxter G . Pre- and postconditioning the heart with hydrogen sulfide (HS) against ischemia/reperfusion injury in vivo: a systematic review and meta-analysis. Basic Res Cardiol. 2017; 113(1):6. PMC: 5730622. DOI: 10.1007/s00395-017-0664-8. View

Zhang B, Jiang H, Chen J, Guo X, Li Y, Hu Q . Nobiletin ameliorates myocardial ischemia and reperfusion injury by attenuating endoplasmic reticulum stress-associated apoptosis through regulation of the PI3K/AKT signal pathway. Int Immunopharmacol. 2019; 73:98-107. DOI: 10.1016/j.intimp.2019.04.060. View

Heusch G . Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2012; 381(9861):166-75. DOI: 10.1016/S0140-6736(12)60916-7. View

Kang B, Hong J, Xiao J, Zhu X, Ni X, Zhang Y . Involvement of miR-1 in the protective effect of hydrogen sulfide against cardiomyocyte apoptosis induced by ischemia/reperfusion. Mol Biol Rep. 2014; 41(10):6845-53. DOI: 10.1007/s11033-014-3570-2. View

Liu H, Tang W, Li C, Lv P, Wang Z, Liu Y . CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats. Nanoscale Res Lett. 2015; 10(1):959. PMC: 4469594. DOI: 10.1186/s11671-015-0959-3. View

10.

Li L, Chen Y, Xu G, Liu D, Yang Z, Chen T . In vivo Comparison of the Biodistribution and Toxicity of InP/ZnS Quantum Dots with Different Surface Modifications. Int J Nanomedicine. 2020; 15:1951-1965. PMC: 7093098. DOI: 10.2147/IJN.S241332. View

11.

Garbayo E, Pascual-Gil S, Rodriguez-Nogales C, Saludas L, de Mendoza A, Blanco-Prieto M . Nanomedicine and drug delivery systems in cancer and regenerative medicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020; 12(5):e1637. DOI: 10.1002/wnan.1637. View

12.

Hu X, Liu B, Wu P, Lang Y, Li T . LncRNA Oprm1 overexpression attenuates myocardial ischemia/reperfusion injury by increasing endogenous hydrogen sulfide via Oprm1/miR-30b-5p/CSE axis. Life Sci. 2020; 254:117699. DOI: 10.1016/j.lfs.2020.117699. View

13.

Shen H, Huang X, Min J, Le S, Wang Q, Wang X . Nanoparticle Delivery Systems for DNA/RNA and their Potential Applications in Nanomedicine. Curr Top Med Chem. 2019; 19(27):2507-2523. DOI: 10.2174/1568026619666191024170212. View

14.

Lei Y, Tang H, Yao L, Yu R, Feng M, Zou B . Applications of mesenchymal stem cells labeled with Tat peptide conjugated quantum dots to cell tracking in mouse body. Bioconjug Chem. 2007; 19(2):421-7. DOI: 10.1021/bc0700685. View

15.

Binder A, Ali A, Chawla R, Aziz H, Abbate A, Jovin I . Myocardial protection from ischemia-reperfusion injury post coronary revascularization. Expert Rev Cardiovasc Ther. 2015; 13(9):1045-57. DOI: 10.1586/14779072.2015.1070669. View

16.

Citi V, Piragine E, Testai L, Breschi M, Calderone V, Martelli A . The Role of Hydrogen Sulfide and H2S-donors in Myocardial Protection Against Ischemia/Reperfusion Injury. Curr Med Chem. 2018; 25(34):4380-4401. DOI: 10.2174/0929867325666180212120504. View

17.

Li J, Zhao Y, Zhou N, Li L, Li K . Dexmedetomidine Attenuates Myocardial Ischemia-Reperfusion Injury in Diabetes Mellitus by Inhibiting Endoplasmic Reticulum Stress. J Diabetes Res. 2019; 2019:7869318. PMC: 6914963. DOI: 10.1155/2019/7869318. View

18.

Kang B, Li W, Xi W, Yi Y, Ciren Y, Shen H . Hydrogen Sulfide Protects Cardiomyocytes against Apoptosis in Ischemia/Reperfusion through MiR-1-Regulated Histone Deacetylase 4 Pathway. Cell Physiol Biochem. 2017; 41(1):10-21. DOI: 10.1159/000455816. View

19.

Neri M, Riezzo I, Pascale N, Pomara C, Turillazzi E . Ischemia/Reperfusion Injury following Acute Myocardial Infarction: A Critical Issue for Clinicians and Forensic Pathologists. Mediators Inflamm. 2017; 2017:7018393. PMC: 5327760. DOI: 10.1155/2017/7018393. View

20.

Xia H, Li Z, Sharp 3rd T, Polhemus D, Carnal J, Moles K . Endothelial Cell Cystathionine γ-Lyase Expression Level Modulates Exercise Capacity, Vascular Function, and Myocardial Ischemia Reperfusion Injury. J Am Heart Assoc. 2020; 9(19):e017544. PMC: 7792404. DOI: 10.1161/JAHA.120.017544. View