作者: Lu, Qing ; Yegambaram, Manivannan ; Moreno Caceres, Santiago ; Wang, Ting ; Fu, Panfeng ; Zemskova, Marina A ; Black, Stephen M. ; Zemskov, Evgeny A. ; Caraballo Delgado, David ; Black, Stephen M ; Zemskova, Marina A. ; Zemskov, Evgeny A ; Wu, Xiaomin

Endothelial cAMP-specific phosphodiesterase PDE3A is one of the major negative regulators of the endothelial barrier function in acute lung injury models. However, the mechanisms underlying its regulation still need to be fully resolved. We show here that the PDE3A is a newly described client of the molecular chaperone heat shock protein 90 (hsp90). In endothelial cells (ECs), hsp90 inhibition by geldanamycin (GA) led to a disruption of the hsp90/PDE3A complex, followed by a significant decrease in PDE3A protein levels. The decrease in PDE3A protein levels was ubiquitin-proteasome-dependent and required the activity of the E3 ubiquitin ligase C terminus of Hsc70-interacting protein. GA treatment also enhanced the association of PDE3A with hsp70, which partially prevented PDE3A degradation. GA-induced decreases in PDE3A protein levels correlated with decreased PDE3 activity and increased cAMP levels in EC. We also demonstrated that protein kinase G-dependent phosphorylation of PDE3A at Ser⁶⁵⁴ can signal the dissociation of PDE3A from hsp90 and PDE3A degradation. This was confirmed by endogenous PDE3A phosphorylation and degradation in 8-Br-cGMP- or 8-CPT-cGMP- and Bay 41-8543-stimulated EC and comparisons of WT- and phospho-mimic S⁶⁵⁴D mutant PDE3A protein stability in transiently transfected HEK293 cells. In conclusion, we have identified a new mechanism of PDE3A regulation mediated by the ubiquitin-proteasome system. Further, the degradation of PDE3A is controlled by the phosphorylation of S⁶⁵⁴ and the interaction with hsp90. We speculate that targeting the PDE3A/hsp90 complex could be a therapeutic approach for acute lung injury.

2024-01-01·Frontiers in pharmacology

Comparison of sGC activator and sGC stimulator in 5/6 nephrectomized rats on high-salt-diet.

Article

作者: Hocher, Berthold ; Krämer, Bernhard K ; Gaballa, Mohamed ; Xiong, Yingquan ; Klein, Thomas ; Kalk, Philipp ; Chen, Xin ; Delić, Denis ; Zeng, Shufei

IntroductionSoluble guanylate cyclase (sGC) stimulators and activators are known to enhance kidney function in various models of chronic kidney disease (CKD) by increasing cyclic guanosine monophosphate (cGMP). Their differential effects on CKD progression, particularly under conditions of oxidative stress, remain unexplored by direct comparative studies.MethodsWe conducted a side-by-side comparison using 5/6 nephrectomized rats on a high salt diet (5/6Nx+HSD) to evaluate the efficacy of the sGC stimulator BAY 41-8543 and the sGC activator BAY 60-2770 in CKD progression. BAY 41-8543 (1 mg/kg; twice daily) and BAY 60-2770 (1 mg/kg; once daily) were administered by gavage for 11 weeks.ResultsThe 5/6Nx+HSD model led to increased plasma creatinine, proteinuria, and blood pressure. Both BAY 41-8543 and BAY 60-2770 significantly reduced systolic and diastolic blood pressure to a similar extent but did not improve renal function parameters. Notably, BAY 60-2770 reduced renal fibrosis, including interstitial fibrosis and glomerulosclerosis, whereas BAY 41-8543 did not. These antifibrotic effects of BAY 60-2770 were independent of blood pressure reduction. Proteomic analysis revealed that BAY 60-2770 corrected the upregulation of 9 proteins associated with apoptosis and fibrosis, including Caspase-3, MKK6 (Mitogen-Activated Protein Kinase Kinase 6), Prdx5 (Peroxiredoxin-5), in the 5/6Nx+HSD group.DiscussionIn contrast, BAY 41-8543 had no significant impact on these proteins. sGC activators were more effective than sGC stimulators in reducing renal fibrosis in 5/6 nephrectomized rats on a high salt diet, and this effect was due to modulation of apoptosis-associated proteins beyond the control of blood pressure.

2023-03-08·JCI Insight

CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling

Article

作者: Schopfer, Francisco J ; Rosas, Lorena ; Mathien, August ; Hahn, Scott A ; Salvatore, Sonia R ; Calyeca, Jazmin ; Uzoukwu, Nneoma ; Baker, Christian ; Straub, Adam C ; Nasser, Amro ; Mays, Brenton G ; Sembrat, John ; Sandner, Peter ; Khaliullin, Timur ; Mora, Ana L ; Shulkowski, Stephanie ; Bueno, Marta ; Alvarez, Diana ; Brands, Judith ; Rojas, Mauricio ; Fiedler, Kaitlin ; Miller, Megan P

Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECIIs. Deficiency of CYB5R3 in AECIIs led to sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and the sGC/cGMP/protein kinase G axis that modulates activation of the TGF-β1 signaling pathway. We demonstrate that sGC agonists (BAY 41-8543 and BAY 54-6544) are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECIIs. Taken together, these results show that CYB5R3 in AECIIs is required to maintain resilience after lung injury and fibrosis and that therapeutic manipulation of the sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.

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适应症	最高研发状态	国家/地区	公司	日期
肺栓塞	临床前	美国	Atrium Health Carolinas Medical Center	2013-09-01
肺栓塞	临床前	美国	The Indiana University School of Medicine	2013-09-01
高血压	临床前	德国	Bayer AG	-