Abstract
Decreased circulating levels of hydrogen sulfide (H2S) are associated with higher mortality following myocardial ischemia. This study aimed at determining the long-term dose-dependent effects of sodium hydrosulfide (NaSH) administration on myocardial ischemia-reperfusion (IR) injury. Male rats were divided into control and NaSH groups that were treated for 9 weeks with daily intraperitoneal injections of normal saline or NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg), respectively. At the end of the study, hearts from all rats were isolated and hemodynamic parameters were recorded during baseline and following IR. In isolated hearts, infarct size, oxidative stress indices as well as mRNA expression of H2S-, nitric oxide (NO)-producing enzymes, and inflammatory markers were measured. In heart tissue following IR, low doses of NaSH (0.28 and 0.56 mg/kg) had no effect, whereas an intermediate dose (1.6 mg/kg), improved recovery of hemodynamic parameters, decreased infarct size, and decreased oxidative stress. It also increased expression of cystathionine γ-lyase (CSE), Raf kinase inhibitor protein (RKIP), endothelial NO synthase (eNOS), and neuronal NOS (nNOS), as well as decreased expression of inducible NOS (iNOS) and nuclear factor kappa-B (NF-κB). At the high dose of 5.6 mg/kg, NaSH administration was associated with worse recovery of hemodynamic parameters and increased infarct size as well as increased oxidative stress. This dose also decreased expression of CSE, RKIP, and eNOS and increased expression of iNOS and NF-κB. In conclusion, chronic treatment with NaSH has a U-shaped concentration effect on IR injury in heart tissue. An intermediate dose was associated with higher CSE-derived H2S, lower iNOS-derived NO, lower oxidative stress, and inflammation in heart tissue following IR.
Highlights
Myocardial ischemia (MI) is one of the leading causes of cardiovascular morbidity and mortality worldwide [1]
In endothelial nitric oxide (NO) synthase-knockout mice, administration of H2S donors failed to protect the heart from IR injury [9]. eNOS-derived NO protected against myocardial IR injury [13,14]; while inducible NOS-derived NO contributed to IR injury [15,16]
NaSH administration for 9 weeks at 0.28–1.6 mg/kg had no significant effects on body weights; at 5.6 mg/kg, it significantly increased heart weight (p = 0.0002), and heart-to-body-weight ratio (p = 0.0004) as assessed at the end of study
Summary
Myocardial ischemia (MI) is one of the leading causes of cardiovascular morbidity and mortality worldwide [1]. Protective effects of ischemic pre-and post-conditioning against myocardial IR injury have been documented in animals [3]; clinical translation of these results has not been very successful [4,5,6]. Another approach for protecting the heart against ischemia is using pharmacological agents, which appears to be a more realistic and feasible approach from the clinical perspective [7]. Inhibition of CSE in mice exacerbated myocardial IR injury by decreasing eNOS-derived NO [9] and increasing iNOS-derived NO [17]. Administration of H2S donors increased tolerance to myocardial IR in rodents by decreasing iNOS expression [18,19] and increasing eNOS activation [9]
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