Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCε in the heart, which are mitigated by endothelin receptor antagonist CPU0213

Abstract

Aim: Spatial dispersion of bioactive substances in the myocardium could serve as pathological basis for arrhythmogenesis and cardiac impairment by β-adrenoceptor stimulation. We hypothesized that dispersed NADPH oxidase, protein kinase Cε (PKCε), early response gene (ERG), and matrix metalloproteinase 9(MMP-9) across the heart by isoproterenol (ISO) medication might be mediated by the endothelin (ET) -ROS pathway. We aimed to verify if ISO induced spatially heterogeneous distribution of pPKCε, NAPDH oxidase, MMP-9 and ERG could be mitigated by either an ET receptor antagonist CPU0213 or iNOS inhibitor aminoguanidine. Methods: Rats were treated with ISO (1 mg/kg sc) for 10 days, and drug interventions (mg/kg) either CPU0213 (30 sc) or aminoguanidine (100 ip) were administered on days 8−10. Expression of NADPH oxidase, MMP-9, ERG, and PKCε in the left and right ventricle (LV, RV) and septum (S) were measured separately. Results: Ventricular hypertrophy was found in the LV, S, and RV, in association with dispersed QTc and oxidative stress in ISO-treated rats. mRNA and protein expression of MMP-9, PKCε, NADPH oxidase and ERG in the LV, S, and RV were obviously dispersed, with augmented expression mainly in the LV and S. Dispersed parameters were re-harmonized by either CPU0213, or aminoguanidine. Conclusion: We found at the first time that ISO-induced dispersed distribution of pPKCε, NADPH oxidase, MMP-9, and ERG in the LV, S, and RV of the heart, which were suppressed by either CPU0213 or aminoguanidine. It indicates that the ET-ROS pathway plays a role in the dispersed distribution of bioactive substances following sustained β-receptor stimulation.

Vascular Endothelial Cells Mediate Mechanical Stimulation-Induced Enhancement of Endothelin Hyperalgesia via Activation of P2X2/3Receptors on Nociceptors

“…As a second measure of loss of an endothelial function we evaluated the effect of octoxynol-9 on the endothelium-dependent (Braquet et al, 1987) plasma protein extravasation induced by platelet-activating factor (PAF) (Mulder and Colditz, 1993; Miao et al, 1996; Cheng et al, 2009). We used PAF to evaluate endothelial cell functional integrity in mediating plasma protein extravasation, as we have extensively used this compound to evaluate plasma protein extravasation (Green et al, 1993a; Green et al, 1993b; Green et al, 1993c; Green et al, 1993d; Green et al, 1994; Green et al, 1995; Green et al, 1997; Green et al, 1998; Lo et al, 1999), while ET-1 itself has not been studied with respect to this function.…”

“…It was somewhat unexpected that inhibition of PKCε did not affect ET-1 hyperalgesia, while BIMM completely eliminated it, especially since ET receptors can signal via PKCε in the heart and arterial smooth muscle cells (Nelson et al, 2008; Cheng et al, 2009; Rainbow et al, 2009) and PKCε is present in nociceptors where its activation can produce sensitization (Parada et al, 2003a; Parada et al, 2003b) as well as contribute to the nociceptor sensitization produced by activation of some of their G-protein coupled receptors (Khasar et al, 1999; Khasar et al, 2008), while other pronociceptive mediators sensitize nociceptors by PKCε-independent second messenger signaling pathways (Pate et al, 2010; Toya and Malik, 2012; Triggle et al, 2012). That BIMM, a non-selective PKC inhibitor (Jang et al, 2008) did attenuate ET-1 induced hyperalgesia does suggest that a non-epsilon isoform of PKC contributes to ET-1-induced nociceptor sensitization and mechanical hyperalgesia.…”

Sildenafil and FDP-Sr attenuate diabetic cardiomyopathy by suppressing abnormal expression of myocardial CASQ2, FKBP12.6, and SERCA2a in rats

“…The PKC/ NFκB/c-fos pathway is activated in neonatal rat cardiomyocytes in high-glucose medium [36] . Activated PKCε has been found in isoproterenol-induced cardiomyopathy and in the vasculature of STZ-injected rats [37,38] . PKCε overexpression may participate in downstream events, including K + channel and calcium-handling protein abnormalities, that are involved in diabetic or isoproterenol-induced cardiomyopathy [9,12,35] .…”

The relationship between the MMP system, adrenoceptors and phosphoprotein phosphatases

“…report that ISO increases MMP‐2 but not MMP‐9 mRNA expression in rats (Kizaki et al ., 2005). While the reason for the lack of effect on MMP‐9 in the latter study is not clear, it may reflect differences in exposure time to ISO (Table 2) or may represent its effects on the spatial dispersion of MMP‐9 in the left ventricle and septum, but not the right ventricle (Cheng et al ., 2009).…”