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Hemoglobin S-nitrosylation plays an essential role in cardioprotection
Rongli Zhang, … , James D. Reynolds, Jonathan S. Stamler
Rongli Zhang, … , James D. Reynolds, Jonathan S. Stamler
Published November 14, 2016
Citation Information: J Clin Invest. 2016;126(12):4654-4658. https://doi.org/10.1172/JCI90425.
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Brief Report Cardiology Vascular biology Article has an altmetric score of 3

Hemoglobin S-nitrosylation plays an essential role in cardioprotection

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Abstract

Homeostatic control of tissue oxygenation is achieved largely through changes in blood flow that are regulated by the classic physiological response of hypoxic vasodilation. The role of nitric oxide (NO) in the control of blood flow is a central tenet of cardiovascular biology. However, extensive evidence now indicates that hypoxic vasodilation entails S-nitrosothiol–based (SNO-based) vasoactivity (rather than NO per se) and that this activity is conveyed substantially by the βCys93 residue in hemoglobin. Thus, tissue oxygenation in the respiratory cycle is dependent on S-nitrosohemoglobin. This perspective predicts that red blood cells (RBCs) may play an important but previously undescribed role in cardioprotection. Here, we have found that cardiac injury and mortality in models of myocardial infarction and heart failure were greatly enhanced in mice lacking βCys93 S-nitrosylation. In addition, βCys93 mutant mice exhibited adaptive collateralization of cardiac vasculature that mitigated ischemic injury and predicted outcomes after myocardial infarction. Enhanced myopathic injury and mortality across different etiologies in the absence of βCys93 confirm the central cardiovascular role of RBC-derived SNO-based vasoactivity and point to a potential locus of therapeutic intervention. Our findings also suggest the possibility that RBCs may play a previously unappreciated role in heart disease.

Authors

Rongli Zhang, Douglas T. Hess, James D. Reynolds, Jonathan S. Stamler

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Figure 3

Assessment of chronic effects of pressure overload (TAC) on mortality and injury in C93A mutant animals.

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Assessment of chronic effects of pressure overload (TAC) on mortality an...
Comparisons among γβC93, βC93A, and γβC93A mice were made following 4 weeks of TAC. (A) A Kaplan-Meier curve illustrates that, within 5 days after TAC, only 1 of 18 γβC93 control animals died (5.6% mortality), whereas 7 of 11 γβC93A mice died (63.6% mortality) before the population stabilized. Also, 12 of 23 βC93A mice died (52.2% mortality), with deaths accumulating over the full TAC time course. (B) Cumulative mortality over 4 weeks was significantly greater for βC93A and γβC93A versus γβC93 mice and did not differ significantly between βC93A and γβC93A mice. *P = 0.0019 vs. γβC93 for γβC93A and **P = 0.0014 vs. γβC93 for γβC93A by Fisher’s exact test (2-sided). (C–F) Echocardiography in mice surviving the 4-week TAC interval revealed greater impairment of LV function in βC93A versus γβC93 mice with respect to ejection fraction (C), fractional shortening (D), cardiac output (E), and end systolic diameter (LV dilation) (F). (G and H) Ratios of heart weight with respect to body weight (G) and lung weight with respect to body weight (H) were significantly increased in βC93A versus γβC93 mice, indicative of increased myocardial hypertrophy and pulmonary edema, respectively. In C–H, n = 11 (γβC93) or 12 (βC93A); P < 0.01 by Student’s t test (2-tailed). (I) Post-mortem examination revealed lung edema and pleural effusion (yellow arrows; a representative βC93A mouse is shown).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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