Cancer therapy, cardiovascular toxicity and hypertension

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1 Cancer therapy, cardiovascular toxicity and hypertension Rhian M Touyz MBBCh, PhD Disclosures: None Capri Cardiovascular Conference 2.0, Capri April 2016

2 Vascular phenotype in hypertension Normotensive Hypertensive Rx Normal Remodeled Endothelial dysfunction Hypercontractile Stiffening/Fibrosis Inflammation

(ERK 1, ERK 2 ) Transcription factors Rec.

3 G protein-coupled receptor and growth factor receptor signaling in hypertension. ANG II, ET-1 RhoA/ Rho kinase Actin- Myosin ROS a g PLC b IP 3 Contraction + PKC + Na + -H + + Ras GTP Raf Ras GDP Pro-rich SOS [Ca 2+ ] i + + MAPK ph i MEK (ERK 1, ERK 2 ) Transcription factors Rec. T.K. P P P P Src PKC IP 3 Jak2 [Ca 2+ ] i STAT 1 STAT 2 Growth factors EGF, VEGF, IL-GF Hyperplasia, Inflammation, Fibrosis ANG II, ET-1

4 Myogenic tone involves EGFR Ang II transactivates EGFR Touyz et al. Hypertension. 2002;39:

5 Genistein (non-specific tyrosine kinase inhibitor) lowers BP in SHR Si. J Nutr. 2008;138

6 GPCR c-src, non receptor tyrosine kinase, and vascular function TKR c-src MAP Kinases p38 MAPK ERK1/2 ERK5 JNK FAK PyK 2 paxillin O 2 O - 2 NADPH + H + NADP + PLC Ca 2+ mobilization proliferation survival cytoskeleton organization cell interaction adhesion migration inflammation oxidative stress VSM ROS

7 Ang II-induced hypertension is attenuated in c-src-deficient mice. SBP (mmhg) SBP (mmhg) SBP (mmhg) SBP (mmhg) A c-src+/- B c-src-/ Days c-src +/+ vehicle c-src +/+ Ang II c-src +/- vehicle c-src +/- Ang II Days c-src +/+ vehicle c-src +/+ Ang II c-src -/- vehicle c-src -/- Ang II C 180 D Days c-src +/+ vehicle c-src +/+ NE c-src +/- vehicle c-src +/- NE Fyn +/+ vehicle Fyn +/+ Ang II Fyn -/- vehicle Fyn -/- Ang II Days Callera, Touyz. 2016

8 VEGF VEGFR Src P P MAPK PI3K P P PLC-g Akt/PKB p-enos NO enos upregula on p-enos PKC Arachidonic acid metabolism Raf1 MEK1/2 ERK1/2 cpla 2 COX-2 Expression NO PGI2 NO IP 3 Ca 2+ p-enos Vasodila on, permeability, cell survival Cameron, Touyz. Can J Cardiol, 20

9 Increased serum VEGF levels in preeclampsia. P<0.001; P< Hunter. Hypertension. 2000;36:

10 Mean arterial pressure in mice treated with DC101 (VEGFR2 antibody). Facemire. Hypertension (3): 652.

11 PIGF VEGF-A VEGF-B VEGF-C/D VEGFR-1 (Flt-1) VEGFR-2 (Flk-1)/KDR VEGFR-3 (Flt-4) Extracellular P P P P PLC (-) Src PI3K P P P P Raf PLC-g P P P P Cell membrane Intracellular Shc Anti/Pro- Angiogenesis Angiogenesis Lymphangiogenesis (Lymph)- angiogenesis Cameron, Touyz. Can J Cardiol, 20

13 Contemporary Chemotherapy

14 USA Cancer Survivors

17 BP and HR in normotensive and hypertensive patients treated with sunitinib for renal cancer Sunitinib Azziz M. New Engl J Med 2008

18 Reversible posterior leukoencephalopathy and VEGFI

19 Probability of survival Increased survival in sorafenib-treated patients who develop hypertension. Hypertension = biomarkers of drug efficacy Motzer. J Clin Oncol. 2009

20 Vasodilatory signaling pathways induced by VEGF Bhargava. Am J Physiol 2009;297

21 VEGF Infusion Induces NO-dependent Hypotension VEGF Infusion decreases BP and increases HR in rabbits NOS inhibition with NG-nitro-L-arginine (L-NNA) reverses effects Horowitz. ATVB. 1997:17

22 Bevacizumab in the Forearm Arterial Circulation VEGF inhibition reduces endothelium-dependent relaxation Thijs A M et al. Hypertension. 2013;61: Thijs. Hypertension2013;61

23 Studying human small arteries ECs VSMC Fibroblasts Local anesthetic Gluteal biopsy Subcutaneous tissue Small resistance artery Cells

24 Inhibition of VEGFR, but not EGFR, reduces enos phosphorylation (active site) p-enos (Ser 1177)/total enos (% of control) vatalanib gefitinib C p-enos (Ser1177) Total enos 135 kda 140 kda cont min vatalanib gefitinib P<0.05 vs control

25 H 2 O 2 Production/Protein ( M/ g) (% control) H 2 O 2 Production/Protein ( M/ g) (% control) Inhibition of VEGFR, but not EGFR, decreases endothelial H 2 O 2 production. 150 Acute 150 Chronic cont min 0 cont h vatalanib gefitinib vatalanib gefitinib

26 Phagocytic Nox Nox isoforms Rac2 Nox2 p67 phox p40 phox p22 phox p47 phox Nox1 p22 phox Rac1 NoxA1 NoxO1 H2O Rac1 Nox3 NoxA1/ p67 phox p22 phox NoxO1/ p47 phox Nox4 p22 phox Nox5 Duox1/2 DuoxA1/2? H 2 O 2 poldip2 O - 2

Nox5 mrna (RQ) Nox4 mrna (RQ) SOD1 mrna (RQ) Vatalanib, but not gefitinib, reduces Nox4 and SOD1 and increases Nox5 expression 2.0 1.5 1.5 1.0 1.0 0.5 0.5 0.0 cont vatalanib gefitinib 0.

27 Nox5 mrna (RQ) Nox4 mrna (RQ) SOD1 mrna (RQ) Vatalanib, but not gefitinib, reduces Nox4 and SOD1 and increases Nox5 expression cont vatalanib gefitinib 0.0 cont vatalanib gefitinib 5.0 VEGFR2 NOX4 4.0? p22pho x ? NOX cont vatalanib gefitinib P<0.05 vs control Catalas e GPX1 H 2 O + O 2 H 2 O 2 Vascular damage? SOD O 2 - Vascular damage

28 HO1 mrna (RQ) NQO1 mrna (RQ) VEGF inhibition reduces anti-oxidant gene expression in endothelial cells. Catalase mrna (RQ) GPX1 mrna (RQ) cont h 0.0 cont h vatalanib gefitinib vatalanib gefitinib cont h 0.0 cont h vatalanib gefitinib vatalanib gefitinib P<0.05 vs control

29 % of relaxation % of relaxation Vatalanib, but not gefitinib, attenuates vasorelaxation in isolated arteries. Endothelium-dependent Endothelium-independent CTRL VAT GEF CTRL VAT GEF Acetylcholine (log M) SNP (log M)

30 VEGF VEGF Traps Aflibercept An -VEGF an bodies Bevacizumab c-srcp P P P PLC PI3K c-src Akt COX-2 ERK1/2 p38mapk Tyrosine kinase inhibitors Suni nib, Sorafenib Raf PLA2 P-eNOS PGI2 NO scg PGI2 H O2 - cgmp Endothelial dysfunc on Vascular remodelling ECM remodelling Vasodila on - Vasoconstric on Cell injury Increased peripheral resistance Hypertension Oxida ve stress 02

31 Inhibi on of VEGF Signalling Endothelial dysfunc on Vascular smooth muscle cell dysfunc on Impaired ECM Vasodilators NO, PGI2 Vasoconstrictors ET-1 Capillary rarefac on VSMC growth, fibrosis, inflammation Oxida ve stress ROS produc on Pressure natriuresis Lymphangiogenesis Systemic and renal vasoconstric on Arterial remodelling Renal dysfunc on ECF buffering Increased peripheral resistance Volume overload Hypertension

32 VEGFR2 expression in small arteries Immunostaining (brown staining) for VEGFR2 IgG control VGFR

Cellular Phenotype in Hypertension Platelet aggregation Endothelial dysfunction Microparticles Vasoactive agents Physical factors BH4 L-arginine Nox ROS O 2-, H 2 O 2 Nox Uncoupled NOS NO Apoptosis,

33 Cellular Phenotype in Hypertension Platelet aggregation Endothelial dysfunction Microparticles Vasoactive agents Physical factors BH4 L-arginine Nox ROS O 2-, H 2 O 2 Nox Uncoupled NOS NO Apoptosis, senescence Growth, Fibrosis Inflammation EDRF EDHF (H 2 O 2?) Constriction Relaxation Monocyte infiltration Rec Ca 2+ RhoA MAPK Rec enos NO NO sgc cgmp GTP Nox ROS ICAM, VCAM PECAM Inflammation Adipocytes Endothelial Dysfunction, Vascular Remodeling

34 Increased endothelial micropraticles post-sunitinib Rx Microparticles x 10 4 /ml platelet MP (x 10 4 /ml) EC MP (x 10 4 /ml) Total number of microparticles in the plasma microparticles derived from endothelial cells ± ± ± ± cycle 1 cycle 2 0 cycle 1 cycle microparticles derived from platelets 310 ± ± cycle 1 cycle 2

35 VEGFR platelets MP (x 10 4 /ml) VEGFR EC MP (x 10 4 /ml) Increased VEGFR2 expression in endothelial micropraticles post-sunitinib Rx VEGFR fluorescence intensity VEGFR fluorescence intensity 5 Microparticles derived from EC that express VEGFR 40 Fluorescence intensity of VEGFR in MP derived from EC ± ± cycle 1 cycle 2 Microparticles derived from PLATELETS that express VEGFR ± ± cycle 1 cycle 2 Fluorescence intensity of VEGFR in MP derived from PLATELETS cycle 1 cycle 2 0 cycle 1 cycle 2

36 Potential mechanisms for VEGF inhibitor-induced hypertension Decreased NOS-NO-mediated dilation Rarefaction Increased arterial stiffness Increased ET-1 Altered renal Na + handling Decreased H 2 O 2 and oxidative stress

37 Bevacizumab Decreases Capillary Density (sidestream dark field imaging of mucosal surface of lip) Baseline 6 weeks Rx Post-Rx

38 Summary & take home message Cross-talk between GPCR and GFRs is important in vascular regulation Tyrosine kinase inhibition reduces BP and improves vascular function. VEGF inhibition increases BP (90% patients) and causes hypertension (30-80% patients) VEGFI-induced hypertension may be a biomarker of effective anti-cancer treatment Factors implicated in VEGFI-induced HT: - NOS activity and vasodilation - H 2 O 2 - oxidative stress and decreased antioxidant status Challenges: Increased cancer survival + increased CVD risk New medical conditions cardiovascular oncology

39 Thanks to: T Univ Glasgow Augusto Montezano Francisco Rios Heather Small Alan Cameron Ninian Lang Sapienza Univ Carmine Savoia Massimo Volpe Funding CIHR HSFC BHF JDRF

Cardiovascular Protection and the RAS

Cardiovascular Protection and the RAS Katalin Kauser, MD, PhD, DSc Senior Associate Director, Boehringer Ingelheim Pharmaceutical Inc. Micardis Product Pipeline Scientific Support Ridgefield, CT, USA Cardiovascular