Targeting neutrophil: new approach against hypertensive cardiac remodeling?

A n association between hypertension and immune system activation has long been recognized as a potential mechanism of hypertensive end-organ damage. Indeed, recent accumulating evidence using mouse models of hypertension induced by angiotensin II (Ang II) supports the roles of T lymphocytes and macrophages in the pathogenesis of hyper-tension and its complications. 1 Curiously, although neutrophil infiltration seems to be the earliest immune and inflammatory response observable with Ang II infusion, limited findings are available regarding the pathophysiological significance of neutrophil accumulation and its signaling mechanism in cardiovascular diseases. Neutrophil-derived myeloperoxidase was shown to be critical for atrial fibrosis and subsequent atrial fibrillation induced by Ang II, which involves hypochlorous acid-induced tyrosine chlorination and activation of matrix metalloprotease-9. 2 Likewise, neutrophil-generated matrix metalloprotease-9 is required for aortic dissection induced by cotreatment with Ang II and a lysyl oxidase inhibitor. Thus, depletion of neutrophils with granulocyte differentiation anti-gen 1 antibody prevented the dissection. 3 However, whether neutrophils and their signal transduction play a role in Ang II–induced hypertensive organ damage had not been investigated. In this issue of Hypertension, Wu et al 4 provide the first compelling evidence supporting that neutrophil-generated S100a8/S100a9 proteins are the key molecules to initiate Ang II–induced cardiac inflammation and fibrosis independently from high blood pressure response. Consistent with the immediate and transient nature of neutrophil activation and infiltration , S100a8/S100a9 mRNAs and proteins demonstrated a sharp rise and fall in cluster of differentiation molecule 11b+/ granulocyte differentiation antigen 1+ neutrophils infiltrating the heart on Ang II infusion. In vitro analysis also showed acute and dominant induction of S100a8 and S100a9 mRNA expression by Ang II in bone marrow–derived monocytes but was relatively lower in cardiac myocytes and cardiac fibro-blasts. S100a8 (calgranulin A or migration inhibitory factor– related protein 8) and its binding partner S100a9 (calgranulin B, or MRP-14) are members of the S100 calcium-binding family of proteins primarily expressed in myeloid cells such as neutrophils and monocytes. These proteins show increased levels in several inflammatory states and have been characterized as significant immune regulatory multifunctional molecules through their intracellular and extracellular actions. 5 They are also recognized as a potential biomarker for the pathophysiological condition including various types of car-diovascular diseases. 5 The intracellular functions of S100a8 include scavenging reactive oxygen species generated by activated neutrophils, whereas the S100a8/S100a9 complex contributes to nicotinamide adenine dinucleotide phosphate oxidase activation in phagocytes. 6 The extracellular functions seem to …