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Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability.
J Am Heart Assoc. 2016 07 05; 5(7)JA

Abstract

BACKGROUND

Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury.

METHODS AND RESULTS

Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R.

CONCLUSIONS

Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.

Authors+Show Affiliations

Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Department of Cardiology, Louisiana State University Health Sciences Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Menarini Ricerche S.p.a., Preclinical Development, Florence, Italy.Department of Pharmacy, University of Naples "Federico II", Naples, Italy.Ochsner Medical Center, New Orleans, LA.Ochsner Medical Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA tgoodc@lsuhsc.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27381758

Citation

Donnarumma, Erminia, et al. "Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury By Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability." Journal of the American Heart Association, vol. 5, no. 7, 2016.
Donnarumma E, Ali MJ, Rushing AM, et al. Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability. J Am Heart Assoc. 2016;5(7).
Donnarumma, E., Ali, M. J., Rushing, A. M., Scarborough, A. L., Bradley, J. M., Organ, C. L., Islam, K. N., Polhemus, D. J., Evangelista, S., Cirino, G., Jenkins, J. S., Patel, R. A., Lefer, D. J., & Goodchild, T. T. (2016). Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability. Journal of the American Heart Association, 5(7). https://doi.org/10.1161/JAHA.116.003531
Donnarumma E, et al. Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury By Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability. J Am Heart Assoc. 2016 07 5;5(7) PubMed PMID: 27381758.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability. AU - Donnarumma,Erminia, AU - Ali,Murtuza J, AU - Rushing,Amanda M, AU - Scarborough,Amy L, AU - Bradley,Jessica M, AU - Organ,Chelsea L, AU - Islam,Kazi N, AU - Polhemus,David J, AU - Evangelista,Stefano, AU - Cirino,Giuseppe, AU - Jenkins,J Stephen, AU - Patel,Rajan A G, AU - Lefer,David J, AU - Goodchild,Traci T, Y1 - 2016/07/05/ PY - 2016/7/7/entrez PY - 2016/7/7/pubmed PY - 2018/1/6/medline KW - antihypertensive agent KW - hydrogen sulfide KW - myocardial ischemia KW - nitric oxide KW - oxidant stress KW - troponin JF - Journal of the American Heart Association JO - J Am Heart Assoc VL - 5 IS - 7 N2 - BACKGROUND: Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine β-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R. CONCLUSIONS: Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling. SN - 2047-9980 UR - https://www.unboundmedicine.com/medline/citation/27381758/Zofenopril_Protects_Against_Myocardial_Ischemia_Reperfusion_Injury_by_Increasing_Nitric_Oxide_and_Hydrogen_Sulfide_Bioavailability_ L2 - https://www.ahajournals.org/doi/10.1161/JAHA.116.003531?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -