inflammatory state in high CV-risk patients: Lp Lp(a) Nederlandse - - PowerPoint PPT Presentation

Targeting cell metabolism to decrease the pro- inflammatory state in high CV-risk patients:

Lp Lp(a)

Jeffrey Kroon, PhD Vascular Medicine, AMC, Amsterdam 4e Nationale Lipidendag 17 mei 2018, Paushuize, Utrecht Nederlandse Lipiden Academie:

None

Disclosures

• LDL-c lowering leads to reduction in CV events
• However, not all events can be prevented by only LCL-c lowering

Circulation 1999;99:736–743. Lancet 1995;345:1274–1275. N Engl J Med 1998;339:1349–1357. J Am Coll Cardiol 1999;33:125–130. N Engl J Med 1995;333:1301–1307. JAMA 1998;279:1615–1622. Lancet 2010;376:333–339.

Lipids in cardiovascular disease

• Not only lipids, but also inflammation plays a crucial role in disease progression

Ross, 1999. N Eng J Med.

Cited > 28.000 times

Inflammation and atherosclerosis

Atherosclerotic lesions are characterized by inflammation Surgeon J. Hudson, 1805 Discussion of inflammatory nature of atherosclerosis reopened in 1999, with first significant review:

Atherosclerosis is characterized by chronic low grade inflammation

• Libbey. Nature. 2002
• Arterial sites of disturbed laminar flow
• Subendothelial accumulation lipoproteins
• Inflammatory mø predominant cells

Inflammation in the driver’s seat

CRP clinically useful as biomarker for risk prediction Inhibiting inflammation the key to the future?

Ridker PM. Circ Res 2016;118:145-156.

IL-1b inhibition as target for atheroprotection

Antiinflammatory therapy targeting led to a significantly lower rate of recurrent cardiovascular events, independent of lipid-level lowering.

Upstream of CRP → IL-1b

MI patients

Cytoskeleton (actin) endothelium Monocyte transendothelial migration Endothelial remodeling during migration

(Immuno)metabolism

Chemo/cytokines

What if we go further upstream…?

Induction of inflammation and production of inflammatory mediators costs energy Lipids Inflammation Cytokine production, migration

(e.g. IL-1b)

Immunometabolism: The changes in intracellular metabolic pathways in immune cells that alter their function 3 major metabolic pathways involved:

• Glycolysis
• Tricarboxylic Acid (TCA) cycle
• Fatty acid oxidation

Complex interplay between metabolic reprogramming and immunity

Immunometabolism

Aerobic Respiration

Link reaction TCA cycle OXPHOS

Kruiswijk et al. Nat Rev. Mol Cel Biol.2015

Glycoylsis 2 ATP 30 ATP

• Palmer. EBioMedicine, 2016

Glut1 transports glucose into the cell

Different metabolic states during lifecycle

Glycolysis TCA/Oxphos

What they encounter determines “who” they becomes

Inflammatory Anti-inflammatory

Can this be used in the clinic?

Van Der Valk et al. Circ 2016. 134(8):611-24

18F-FDG PET/CT-scan Yellow = metabolic activity

Increased glucose uptake in carotid and aorta (=increased glycolysis)

Lp(a) patients have increased vessel wall inflammation measured with 18F-FDG PET/CT-scan

What is the effect of this increased glycolysis?

Increased expression of

• Chemokines
• Adhesion markers

Van Der Valk et al. Circ 2016. 134(8):611-24

CCR7 CCR7 CD CD29

Lp(a) patients have ‘pro-inflammatory’ monocytes

Functional differences in monocyte behavior?

Hoog lp(a) Laag lp(a)

Van Der Valk et al. Circ 2016. 134(8):611-24

Lp(a) patients have ‘pro-migratory’ monocytes ex-vivo

1. 2. 3. 4.

1. 2. 3. 4.

Increased monocyte activation Enhanced adhesion and transmigration across the endothelium Increased production of pro-inflammatory cytokines Elevated inflammatory activity of the arterial wall (PET/CT)

Sub-conclusion: Lp(a) & Inflammation

Metabolism?

Lp(a)

inflammation Cytokine production, migration

individual with elevated Lp(a) levels blood withdrawal Lp(a) arterial endothelium monocytes

Metabolic reprogramming

Lp(a)-induced metabolic reprogramming

Lp(a) induces endothelial cell inflammation and monocyte migration

Rolling

Firm adhesion

100 mg/dL Lp(a)

Kroon et al. Int. Rev.

• Cell. Mol. Biol. 2016

Chemokine activation Firm adhesion Migration

Does this coincide with metabolic reprogramming?

Firm adhesion

Chemokine activation Firm adhesion Migration unstim. Lp(a)

Green labeled glucose

Glucose uptake Lactate production

Lp(a) induces endothelial cell metabolic reprogramming Inhibition?

Inhibition glycolysis

Targeting cell metabolism decreases inflammation and migration

Firm adhesion

• Unstim. Lp(a) Lp(a)

+ inhib

• Unstim. Lp(a) Lp(a)

+ inhib

Migration

unstim. Lp(a) Lp(a) 1 2 3 4 5 6

Transmigrated monocytes (normalized)

• Unstim. Lp(a)

Lp(a) + inhib

Clinical perspective of inhibition of inducible glycolysis

• Selective inhibitor of inducible glycolysis:

basal glycolytic rate not affected

PFK-158

Endothelial viability after 24h of inhibitor

Possibly the new era of cardiovascular intervention

• Promising completed phase I trial

in cancer patients with various solid

• tumors. No side effects reported

(Experimental) Vascular Medicine, AMC Jan Schnitzler Julian Bachmann Miranda Versloot Renate Hoogeveen Bert Groen Erik Stroes Genetic Metabolic Diseases, AMC Riekelt Houtkooper Michel van de Weeghel UCSD, San Diego, USA Sam Tsimikas Joe Witztum Robarts Research Institute, Ontario, Canada Marlys Koschinsky

Acknowledgements