Nitrite Improves Heart Regeneration in Zebrafish

Abstract

Aims: Nitrite is reduced to nitric oxide (NO) under physiological and pathological hypoxic conditions to modulate angiogenesis and improve ischemia-reperfusion injury. Although adult mammals lack the ability to regenerate the heart after injury, this is preserved in neonates and efforts to reactivate this process are of great interest. Unlike mammals, the adult zebrafish maintain the innate ability to regenerate their hearts after injury, providing an important model to study cardiac regeneration. We thus explored the effects of physiological levels of nitrite on cardiac and fin regeneration and downstream cellular and molecular signaling pathways in response to amputation and cryoinjury. Results: Nitrite treatment of zebrafish after ventricular amputation or cryoinjury to the heart in hypoxic water (*3 parts per million of oxygen) increases cardiomyocyte proliferation, improves angiogenesis, and enhances early recruitment of thrombocytes, macrophages, and neutrophils to the injury. When tested in a fin regeneration model, neutrophil recruitment to the injury site was found to be dependent on NO. Innovation: This is the first study to evaluate effects of physiological levels of nitrite on cardiac regeneration in response to cardiac injury, with the observation that nitrite in water accelerates zebrafish heart regeneration. Conclusion: Physiological and therapeutic levels of nitrite increase thrombocyte, neutrophil, and macrophage recruitment to the heart after amputation and cryoinjury in zebrafish, resulting in accelerated cardiomyocyte proliferation and angiogenesis. Translation of this finding to mammalian models of injury during early development may provide an opportunity to improve outcomes during intrauterine fetal or neonatal cardiac surgery. Antioxid. Redox Signal. 32, 363-377.

Preclinical Study on the Ameliorating Effect of L-Ascorbic Acid for the Oxidative Stress of Caused by Chronic Administration of Organic Nitrates in Cardiovascular Diseases

“…Increased methemoglobin level can cause congenital enzymatic defects, variation in hemoglobin molecule [41,42]. Methemoglobin does not bind to oxygen e ciently causing a Loading [MathJax]/jax/output/CommonHTML/jax.js reduction in the oxygen carrying capacity of the blood and reduction in saturated oxygen and oxygen content this decrease is signi cant in high doses of nitrates [43]. Vitamin C protects the blood from the oxidant effect of nitric oxide (antioxidant effect) and induces decreasing of level of met-hemoglobin concentration [42].…”

“…This reduction in methemoglobin levels induced by vitamin C concluded that erythrocyte alone had a negligible ability to reduce methemoglobin in the absence of exogenous ascorbate. Ascorbic acid preserves the Hb in a reduced ferrous redox state [43,44].…”

Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury

“…However, it also plays other less known physiological roles, including in the cardiovascular system, where it lowers blood pressure, induces negative inotropic and chronotropic effects, and serves as an anti-inflammatory and anti-oxidant (Garrott et al, 2017; Gutkowska et al, 2014; Jankowski et al, 2020). Many of these actions are carried out by OXT-mediated release of atrial natriuretic peptide (ANP) and nitric oxide (NO) (Jankowski et al, 2020), which have well-characterized cardioprotective effects (Jones & Bolli, 2006; Nishikimi et al, 2006) and may themselves contribute to heart regeneration (Kook et al, 2003; Rochon et al, 2020). Notably, OXT also induces differentiation of cardiomyocytes from embryonic stem cells (Paquin et al, 2002).…”

Hooked on heart regeneration: the zebrafish guide to recovery

“…Earlier this year, it was described how nitric oxide—the reduced form of nitrite, which occurs under hypoxic conditions—improved angiogenesis, immune cell recruitment, and cardiomyocyte proliferation following both cryoinjury and ventricular resection. 76 …”