The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction

Figures

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  Figure 1. Molecular mechanisms of cardiomyocytes protection against MIRI and the potential effect of concomitant NEP inhibition/AT1R antagonism. NEP inhibition by sacubitril leads to increased levels of plasmatic Ang II, Bk, SP, NPs, ADM, and apelin. Increased Ang II levels, through a PKCε dependent mechanism, lead to the AT1R and AT2R translocation from plasmatic to mitochondrial membrane where they exert their protective role. In particular, plasmatic AT1Rs stimulate NOS activity leading to superoxide generation, mitochondrial K+-ATP channel activity, membrane depolarization, and MPTPs opening. This process enhances the efflux of superoxide into the cytoplasm and promotes the activation of pro-survival kinases. By contrast, plasmatic AT2R stimulation leads to NOS-NO-PKG stimulation that further stimulates PKCε. In the mitochondria, the up-regulation of AT2R/AT1R protein levels controls the MRC activity through a stimulatory mechanism composed of ROS and an inhibitory pathway involving NOS-NO. This latter exerts a master control on respiratory function as it modulates AT1Rs, while tonically suppressing electron transport chain activity. Concomitant inhibition of AT1R by valsartan blocks…

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  Figure 2. Repeated episodes of hypoxia-reoxygenation enhance the synthesis and the release in the extracellular space of bradykinin (Bk), through an increase of tissue kallikrein 1 (KLK1) activity. The released Bk by an autocrine mechanism binds its receptors. These consist of 2 types of seven transmembrane domain G protein-coupled receptors: type 2 (BKR2), which is constitutively expressed; and type 1 (BKR1), which is not constitutively expressed, but it is up-regulated by late PC. The binding of Bk to BKR2 induces the endocytosis of the receptor; this phenomenon activates protein kinase A (PKA), which, in turn, phosphorylates/activates Akt. This mechanism accounts for the cytoprotective effect of the early and late preconditioning (PC). The binding of Bk to BKR1 through the activation of PKA-Akt accounts for cytoprotection in the late window of PC.

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  Figure 3. Protective effects of apelins against MIRI. A large body of evidence suggests that apelin-12, -13, and -36 ameliorate MIRI. These apelin isoforms trigger inhibition and activation pathways during MIRI. In particular, they inhibit MPTPs opening, ROS formation, and ER stress. Consistently, they activate ionic channel function for ion homeostasis, NO synthesis, and angiogenesis. All these effects protect the heart against MIRI. MIRI, myocardial ischemia-reperfusion injury; MPTPs, mitochondrial permeability transition pores; ROS, reactive oxygen species; ER, endoplasmic reticulum; NO, nitric oxide.