Neutrophil-Initiated Myocardial Inflammation and Its Modulation by B-Type Natriuretic Peptide: A Potential Therapeutic Target

Abstract

Activation of neutrophils is a critically important component of the innate immune response to bacterial and chemical stimuli, and culminates in the "neutrophil burst", which facilitates neutrophil phagocytosis via the release of superoxide anion radical (O₂^-) from NADPH oxidase. Excessive and/or prolonged neutrophil activation results in substantial tissue injury and increases in vascular permeability-resulting in sustained tissue infiltration with neutrophils and monocytes, and persistent vasomotor dysfunction. Cardiovascular examples of such changes include acute and chronic systolic and diastolic heart failure ("heart failure with preserved ejection fraction"), and the catecholamine-induced inflammatory disorder takotsubo syndrome. We have recently demonstrated that B-type natriuretic peptide (BNP), acting via inhibition of activation of neutrophil NADPH oxidase, is an important negative modulator of the "neutrophil burst", though its effectiveness in limiting tissue injury is partially lost in acute heart failure. The potential therapeutic implications of these findings, regarding the development of new means of treating both acute and chronic cardiac injury states, are discussed.

Keywords: BNP; heart failure; takotsubo syndrome; “neutrophil burst”.

Figure 1

Cascade of intracellular and extracellular consequences of redox stress related to neutrophil activation. SOD = superoxide dismutase; MPO = myeloperoxidase; TXNIP = thioredoxin-interacting protein; NLRP3 = NOD-like receptor family, pyrin domain-containing 3.

Figure 2

Cascade of BNP release and consequent physiological effects and clearance. BNP = B-type natriuretic peptide; NPR-C = natriuretic peptide receptor C; NEP = neutral endopeptidase; DPP IV = dipeptidyl peptidase IV; IDE = insulin degrading enzyme; pGC = particulate guanylate cyclase; PDE = phosphodiesterase; GTP = guanosine triphosphate; cGMP = cyclic guanosine monophosphate.

Figure 3

Comparison of BNP effects on phorbol 12-myristate 13-acetate (PMA)-stimulated (A) and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated (B) O₂⁻ generation by neutrophils from acute heart failure patients (n = 45) and control subjects (n = 29). (C,D) Raw data for actual O₂⁻ production in neutrophils from acute heart failure patients (C) and control subjects (D). * p < 0.05 [14].

Figure 4

Effect of BNP on phosphorylation of p47phox Ser345. (A) In acute heart failure patients (n = 9) there is attenuation of BNP-induced suppression of p47phox Ser345 phosphorylation stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP), which is seen in neutrophils from healthy subjects (n = 7). The relative ratio of p47phox Ser345 to total p47phox for samples treated with fMLP was taken as control (100%). * p < 0.05. (B) Representative immunoblots of acute heart failure patients and control subjects. Note suppression of phosphorylation of Ser345 by BNP in control subjects but not acute heart failure patients [14].