Prolactin and its cleaved 16-kDa subform. enhance myocardial injury after ischemia/reperfusion
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1 Prolactin and its cleaved 16-kDa subform enhance myocardial injury after ischemia/reperfusion Hatice Yamac, Denise Hilfiker-Kleiner Department of Cardiology & Angiology Hannover, Medical School There is no conflict of interest
2 Prolactin is a member of the growth hormone family responsible for the coordination of a wide range of biological processes: Fertility, lactation, tumor growth, immunity and inflammation, hemodynamics.
3 Pro- and anti-angiogenetic effects of the pregnancy and nursing hormone prolactin 16-kDa prolactin acts as a potent inhibitor of angiogenesis Linda Schuler; Corbacho A.M. et al., J Endocrinol 22
4 16-kDa Prolactin decreases cardiac capillary density, increases cardiac apoptosis, attenuates cardiac function, and promotes LV dilatation 16-kDa Adenovirus Prolactin *P<.5 %FS LVESD Prolactin LacZ Adenovirus (%) LacZ-Ad (mm) 3, 2,6 * 2,2 1,8 1,4 1, 16K-Ad LacZ-Ad * 16K-Ad (%) 12 8 Capillaries/Cardiomyocytes * *P<,5 Con LacZ 16kDa 16-kDa act-casp-3 4 LacZ-Ad 16-K-Ad Hilfiker-Kleiner et al. Cell 27
5 Evidence for Prolactin cleavage in the heart? Pituitary gland Endothelial cell 23 kda Prolactin MMPs active CD 16-kDa Prolactin Apoptosis Dissociation of capillary structures Vasoconstriction Inflammation PPCM Fibroblast active CD STAT3 Mitochondrium MnSOD ROS inactive CD Reduced metabolism Affected function Cardiomyocyte Yamac and Hilfiker-Kleiner, Heart 21
6 Does 16-kDa Prolactin play a role in cardiac ischemia reperfusion injury? Oxidative Stress Cathepsin D 16-kDa Prolactin Inflammation Reduced Metabolism Endothelial cell apoptosis
7 Fold induction Prolactin in ng/ml CD activity in RU Enhanced generation of 16-kDa Prolactin in patients with acute MI (AMI) 1 8 Serum total Prolactin P<.1 vs Co ## P<.1 pd vs AMI 5 4 Serum Cathepsin D activity P<.1 vs Co ## P<.1 pd vs AMI ## 2 1 ## Controls controls acute AMI MI pre-discharge Controls AMI pre-discharge Immunoprecipitation of serum 16-kDa prolactin 1 8 P< kDa Prl 2 Controls AMI/IgG AMI Controls controls AMI
8 Prolactin in ng/ml Similar to patient data: serum Prolactin, Cathepsin D activity and 16-kDa Prolactin are increased in acute MI followed by reperfusion () CD activity in RU Serum total Prolactin Serum Cathepsin D activity IP of serum 16-kDa Prolactin 28 * * CO 1 Sh *P<.5 vs CO Time/h Time/h *P<.5 vs CO * * * Sh IgG 4 16-kDa Prl 2 CO 1 Sh Time/h Time of ischemia by LAD occlusion: 5 min
9 Fold induction CD activity in RU Cathepsin D activity and 16-kDa Prolactin levels are increased in borderzone and ischemic zone after 16-kDa expression in LV-tissue Cathepsin D activity in LV-tissue CO Sh 6 4 P<.1 vs Co 16-kDa Prl Ponceau Time/h P<.1 vs CO CO 1 Sh Time/h CO 1 Sh Time/h kDa staining in LV-tissue CO
10 NOX +GST NOX+GST NOX NOX+Prl +Prl CD activity in RU NOX NOX+Prl +Prl promotes binding of Prolactin to cardiomyocytes and enhances its cleavage into the 16-kDa subform Neonatal Cardiomyocytes 23-kDa Prl 16-kDa Prl Supernatant CD activity in cell supernatant 12, 8, 23-kDa Prl 16-kDa Prl Whole cell-lysate 4, *, NOX Time/h P<.1 vs NOX GST
11 Hypothesis The generation of 16kDa Prolactin from 23kDa full length Prolactin after oxidative stress (Mouse Ischemia/reperfusion model) might responsible for adverse cardiac effects. Inhibition of Prolactin secretion by the dopamine D2 receptor agonist Bromocriptine should eliminate both Prolactin forms and subsequently injury should be reduced. Treatment of SV129 male mice with Bromocriptine, a pharmacological inhibitor of Prolactin secretion. 4 mg/kg/d, 5 days before till 24 h to 14 d after ischemia/reperfusion
12 Bromocriptine prevents increase of full-length and 16-kDa Prolactin levels in serum but has no effect on Cathepsin D activity after CD activity in RU Prolactin in ng/ml Serum total Prolactin CO Sh ;BR * *P<.5 vs Co # P<.5 vs # 6 4 Serum Cathepsin D activity P<.5 vs CO 2 CO CO/BR Sh Sh/BR ;BR Immunoprecipitation of serum Prolactin 23-kDa Prl 16-kDa Prl ;BR ;IgG Sh
13 Bromocriptine prevents increase 16-kDa Prolactin levels but has no effect on Cathepsin D activity in cardiac tissue after CD activity in RU Cathepsin D activity in LV tissue 6 4 P<.5 vs Sh 2 Sh ;BR Co MI BR/MI Left ventricular 16-kDa prolactin expression Sh Time/h kDa Prl Ponceau Bromocriptine Left ventricular 16-kDa prolactin expression 16-kDa Prl Bz Ax Bz Ax Bz Ax Ponceau ;BR Sh
14 ctri (%) Infarction size (%) Blockage of Prolactin release by bromocriptine attenuates induced myocardial injury Infarction size/area at risk ;BR 1 8 AAR MI/AAR P< ;BR Cardiac Troponin I * Co ;BR Br *P<.5
15 Infarction size (%) Smaller infarct sizes persist and are associated with better cardiac function 14 days after reperfusion in the bromocriptine treated group Infarction size/heart 14d 4 *P<.5 ;BR 3 2 * 1 1 ;BR 2 # P<.5 vs baseline P<.5 vs Co after Control-group baseline Control-group after Bromocriptinegroup baseline Bromocriptine group after IVSD 1,12 ±,18 1,2 ±,17 1,24 ±,17 1,24 ±,13 LVEAD 2,95 ± 4,5 23,6 ± 6,25 2,6 ± 3,1 19,8 ± 4,3 LVEAS 9,6 ± 2,5 15,1 ± 6,1 8,9 ± 18 9, ± 2,9 FAC 54,3 ± 4,2 37,6 ± 9,5 # 57,2 ± 3,6 54,9 ± 6,3 HR 445 ± ± ± ± 34
16 Which Prolactin form is mainly responsible for injury? Pituitary gland? 23 kda Prolactin MMPs active CD? 16 kda Prolactin Endothelial cell Apoptosis Dissociation of capillary structures Vasoconstriction Inflammation injury Fibroblast active CD Oxidatives stress ROS inactive CD Reduced metabolism Affected function Cardiomyocyte Adapted from Yamac and Hilfiker-Kleiner, Heart 21
17 Mutation of Cathepsin D cleavage site in Prolactin prevents its efficient cleavage into the 16-kDa subform Piwnica, Endocrinology 24 Prolactin cleavage at ph 5 Prolactin cleavage in BZ at ph 7 23-kDa Prl rwt-p rl146-p rwt-p Pep A RM BZ IS SH BZ BZ/P BZ BZ/P rl146-p rwt-p rl146-p rwt-p 23-kDa Prl 16-kDa Prl 16-kDa Prl RM: REMOTE MYOCARDIUM, BZ: BORDERZONE IS: ISCHEMIC MYOCARDIUM, P: PEPSTATIN A
18 Experimental setting L146P Prl Non-cleavable prolactin rwt Prl Prolactin effectively processed into 16-kDa form 16 kda Day 1 Day 5 Day8 Day 9
19 ctri (%) Infarction size (%) Enhanced 16-kDA Prolactin cleavage promotes myocardial injury after ;BR;rWT ;BR;rL146P 1 8 AAR MI/AAR Infarction size/area at risk P<.5 vs rwt P<.1 vs ;BR ;BR, rwt ;BR, rl146p Cardiac Troponin I * *P<.5 L146P Prl Non-cleavable prolactin rwt Prl Prolactin effectively processed into 16-kDa form rwt ;BR rwt rl146p ;BR rl146p
20 How does 16-kDa Prolactin promote injury of the heart? Pituitary gland 23 kda Prolactin 16 kda Prolactin Apoptosis Inflammation MMPs active CD injury Fibroblast active CD Oxidatives stress ROS inactive CD Reduced metabolism Affected function Cardiomyocyte Adapted from Yamac and Hilfiker-Kleiner, Heart 21
21 16-kDa Prolactin promotes apoptosis in endothelial cells...
22 ... but not in cardiomyocytes Neonatal Cardiomyocytes % 15 Tryphan blue-staining 1 5 P<.1 vs NOX Normoxia
23 Inflammation and injury Reduced Myocardial Ischemia-Reperfusion Injury in Toll-Like Receptor 4- Deficient Mice Jun-ichi Oyama, MD; Charles Blais, Jr, PhD; Xiaoli Liu, MD; Minying Pu, MD; Lester Kobzik, MD; Ralph A. Kelly, MD; Todd Bourcier, PhD. Circulation 24. Endothelial Cell Overexpression of Fas Ligand Attenuates Ischemia- Reperfusion Injury in the Heart Jiang Yang, Steven P. Jones, Toshimitsu Suhara, James J. M. Greer, Paul D. Ware, Nhan P. Nguyen, Harris Perlman, David P. Nelson, David J. Lefer and Kenneth Walsh. JBC 23. Anti-tumor necrosis factor-alpha improves myocardial recovery after ischemia and reperfusion J Gurevitch, I Frolkis, Y Yuhas, B Lifschitz-Mercer, E Berger, Y Paz, M Matsa, A Kramer, and R Mohr. JACC 1997.
24 Prolactin and 16-kDa Prolactin enhance cardiac inflammation after CD45 MOMA CO ;BR CD 45 staining ;BR ;BR rwt ;BR rl146p ;BR rwt ;BR rl146p % 4 CD 45 P<.1 vs NaCl % 16 MOMA P<.5 vs rwt P<.1 vs rwt * *P<.5 vs NaCl Sham NaCl CO NaCl BR rwt-p rl146-p rl146p Sh 1 NaCl 2 NaCl 3 rwt-p 4 rl146-p 5 BR BR
25 Fold induction Fold induction Fold induction Fold induction Prolactin and 16-kDa Prolactin enhance inflammatory cytokines and chemokines expression after 25 TNF-alpha 2 IL # # 1 5 Sh 1 2 ;BR 3 ;BR 4 ;BR 5 rwt rl146p Sh 1 2 ;BR 3 ;BR 4 ;BR 5 rwt rl146p CCL-2 ## ## CXCL2 ## ## Sh 1 2 ;BR 3 ;BR 4 ;BR 5 rwt rl146p Sh 1 2 ;BR 3 ;BR 4 ;BR 5 rwt rl146p P<.1 vs Sh # P<.5 vs ## P<.1 vs P<.5 vs rwt
26 16-kDa Prolactin induces expression of proinflammatiory cytokines and chemokines in cultured cardiomyocytes Fold induction Fold induction Fold induction Fold induction CCL-2 CO 1 r16-kda 2 rwt 3 Prl CXCL2 CO 1 r16-kda 2 rwt 3 Prl 4 3 TNF alpha 15 1 IL CO1 r16-kda 2 rwt 3 Prl CO 1 r16-kda 2 rwt 3Prl P<.1 vs CO
27 Fold induction 16-kDa Prolactin up-regulates the pro-inflammatory CCL2 via activation of NFκB CO r16-kda IκB Actin CCL-2 1h CO r16-kda 2 CO 1 BAY 2 r16-kda 3 BAY+ 4 r16-kda P<.1 vs CO P<.1 vs r16-kda 2 h
28 Summary and Conclusion Transiently elevated prolactin levels and cathepsin D activity in sera of patients with acute myocardial infarction are associated with the generation of the cleaved anti-angiogenic and pro-inflammatory 16-kDa prolactin. Systemic prolactin blockage by the dopamin D2 receptor agonist bromocriptine reduces infarction size and improves cardiac function after in mice. Prolactin dependent myocardial damage in mainly derives from the cleaved 16-kDa prolactin fragment. 16-kDa prolactin promotes cardiac inflammation by up-regulation of cytokine and chemokine expression in cardiomyoctes in vitro and in the heart in vivo. 16-kDa prolactin promotes up-regulation of pro-inflammatory CCL2 via activation of NFκB dependent in cardiomyoctes.
29 Clinic for Cardiology & Angiology Molecular Cardiology, Hannover Denise Hilfiker-Kleiner J. Wibbe S. Erschow M. Kasten Y. Marquard I. Renger I. Bultmann S. Labidi Liège, B I. Struman Inserm, Paris, F V. Goffin
30 BACKUPS
31 Do cardiomyocytes generate prolactin and its subform? Oxidative stress injury Hilfiker-Kleiner et al. Future Cardiology 29
32 Cardiomyocytes produce 16-kDa Prolactin 12, 8, 4,,
33 MCP1 CO NaCl Curcumin MCP1 Ponceau BR; WT Prl
34 NOX +GST NOX+GST NOX +Prl NOX+Prl GST/PRL 23-kDa Prl 16-kDa Prl 23-kDa Prl 16-kDa Prl Supernatant Whole cell-lysate GST
35 CO r16-kda rl146p Prl rwt Prl CO r16-kda rl146p Prl rwt Prl Fold induction 1 8 MCP1 6 * # Normoxia
36 16kDa Prolactin interfers with endothelial Ca 2+ transients and disturbs vasorelaxation
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