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  • The reduction of heterodimerization of KOR and

    2024-06-12

    The reduction of heterodimerization of KOR and APJ by both doses of apelin found in the present study may result in inducing protective effects of apelin on the myocardium imposed to high pressure in renovascular hypertension conditions. The finding that apelin in both doses reduced heterodimerization (Fig. 6C) and increased myocardial contractility (Figs. 3B and 5B) imply that increased dimerization may induce negative inotropic effects of apelin. Interestingly the inotropic effects of apelin that were inhibited by F13A and nor-BNI were recovered when both these receptors were inhibited simultaneously (Fig. 5A,B). The increased level of pERK1/2 is one of the downstream signaling pathways in which apelin increases the cardiac contractility [8]. The level of pERK1/2 reduced in response to the increase in pressure load imposed to the Vidofludimus (Fig. 7A). Many studies indicated the activation of ERK1/2 signaling pathway during the development and stabilization of cardiac hypertrophy in response to hypertension [22], [23]. However, the inhibition of ERK1/2 activity did not prevent the hypertrophy in response to different hypertrophy stimuli. Hence, reduction in pERK1/2 found in the present study may participate in the complications of hypertrophy in chronic renovascular hypertension. Both doses of apelin normalized the heterodimerization of APJ and KORs (Fig. 6C) as well as the level of pERK1/2 (Fig. 7) through which they could save their positive inotropic and lusitropic effects on the hypertrophied heart that is in the risk of failure in these conditions (see increase in cardiac diameter in Fig 1B and F). The cardiac hypertrophy of this model of hypertension (see increase in myocytes diameter and left ventricular wall thickness, Fig. 1) may have been produced through malfunction of the ERK1/2 pathway. Accumulating lines of evidence suggest that PKC and ERK1/2 cascades constitute important adaptive mechanisms in the myocardium under pathological conditions [8]. As an example, PKC and ERK1/2 signalings have been reported to confer cardio protection in vivo against ischemia-reperfusion injury by reducing cell death [24]. The inhibition of apelin receptors by F13A could not prevent the increase in pERK1/2 in response to apelin in both doses (Fig. 7A, B), but it inhibited the increase of contractility in response to apelin stimulation (Figs. 3B and 5B). The contradiction may result from the point that apelin can also increase cardiac contractility via another signaling pathway (PKC) which acts parallel with ERK1/2 [8]. It has been shown that APJ protomer form homo- and heterodimers with other GPCRs such as KORs. Since GPCR heterodimerization can modify receptor function by modulating ligand binding and receptor activation, one may concluded that the relative cell surface density of APJ homodimers versus heterodimers could explain the unexpected effects of F13A observed [25]. Therefore, probably apelin increased cardiac contractility via APJ protomer that was inhibited by F13A. Phosphorylation of ERK1/2 in response to apelin is mediated by heterodimeric form of apelin receptor that is not inhibited by F13A. The inhibition of KOR prevents inotropic and lusitropic effects of apelin 60 and intensifies ERK1/2 phosphorylation. (see Figs. 4D and 7B). KORs may modify the response to apelin through the inhibition of excessive pERK1/2 production. It has been shown that GPCR dimerization alters downstream intracellular signaling, desensitization and internalization [26]. It is probable that KORs and APJ dimerization modify coupling of APJ to Go or Gq/11 rather than β-arrestin. In the presence of nor-BNI, APJ is coupled with β-arrestin and increase ERK1/2 phosphorylation. It has been shown that apelin-13 can activate ERKs in a G-protein and β-arrestin dependent manner [27], [28]. Therefore, KORs may mediated cardiac contractility by switching between the G protein–dependent and β-arrestin dependent pathways and prevents hypertrophy caused by higher doses of apelin. The finding that PTX does not inhibit the effect of low dose apelin on ERK, but inhibit the effect of high dose (Fig. 7) may imply that Gαi signaling is also involved.