223stress. Neurons treated with 10 nM pGlu-serpinin in the presence of H 2 O 2 showed
no difference in MAP 2 (a neuronal marker) signal compared to non-treated control
neurons, but neurons treated with H 2 O 2 showed a significant reduction in MAP2
signal (Fig. 11A; Koshimizu et al. 2011b). The neuroprotective effect of pGlu-
serpinin is mediated by up-regulating the expression of the pro-survival mitochon-
drial protein, BCL2, in neurons under H 2 O 2 induced oxidative stress (Fig. 11B; Loh
et al. 2012a). Additionally, pGlu-serpinin also showed significant cardioprotective
effects after ischemic stress of the rat heart ((Pasqua et al. 2015 ), see also chapter
“Full Length CgA: A Multifaceted Protein in Cardiovascular Health and Disease”
by B. Tota). Serpinin and pGlu-serpinin peptides have also been found to be positive
cardiac β-adrenergic-like inotropes having a powerful effect on enhancing myocar-
dial contractility and relaxation without change in blood pressure (Tota et al. 2012 ).
The cAMP-PKA signaling pathway is also activated by serpinin and pGlu-serpinin
to mediate inotropic activity in the heart (Tota et al. 2012 , see Tota’s chapter “Full
LengthCgA: A Multifaceted Protein in Cardiovascular Health and Disease”).
Fig. 8 Serpinin induces PN1 mRNA by a cAMP/PKA/SP1 signaling pathway. (A) PN1 mRNA is
upregulated in AtT20 cells by 8-Br-cAMP and forskolin. (B) Intracellular cAMP increases in
AtT20 cells treated with serpinin. (C) The PKA inhibitor, 6.22 amide, blocked the serpinin-induced
up-regulation of PN1 mRNA. (D) Serpinin treatment of AtT20 cells induced the translocation of
SP1 into the nucleus. Arrow heads indicate nuclear staining of SP1 immunoreactivity E.
Mithramycin A (MitA), a specific inhibitor of SP1 binding, inhibits the serpinin-induced expres-
sion of PN1 mRNA (From Koshimizu et al. 2011a)
Serpinin Peptides: Tissue Distribution and Functions