The strange case of Dr HDL and Mr HDL: does a NO's story illuminate the mystery of HDL's dark side uncovered by Dr HDL's drug targeting CETP?
Recently, the first large-scale morbidity and mortality trial (ILLUMINATE) to evaluate the cardiovascular end points of a CETP inhibitor (torcetrapib) has been prematurely stopped because the mortality was significantly increased in the treated group. Why torcetrapib caused excess death is not known. Based on the fact that HDL interacts with endothelial nitric oxyde synthase (eNOS) and nitric oxide (NO) secretion, which partly controlled blood pressure and than torcetrapib could increase blood pressure among some patients, we hypothesize that CETP inhibition could have significantly inhibit eNOS. CETP inhibition would have enlarged HDL size resulting in a deficit in the interaction between HDL and the Scavenger Receptor class B type I (SR-BI), which is an important link between HDL and eNOS activation. We suggest than the deficit in NO secretion would have been sufficient among all patients to induce a destabilization of the plaques of atheroma, but could have induced a pathogenic increase in blood pressure only in patients whose eNOS activity was naturally weak due to genetic polymorphisms of this enzyme. We also hypothesize that the increase in HDL levels, induced by CETP inhibition, coupled with the capacity of HDL to induce endothelin-1 secretion would have aggravated the cardiovascular risks under this CETP inhibitor treatment.
Duriez
Patrick
P
Université de Lille 2, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, F-59006, France. Patrick.Duriez@univ-lille2.fr
Bordet
Régis
R
Berthelot
Pascal
P
D000924:Anticholesteremic Agents / Q000627:therapeutic use; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood*; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood* / Q000187:drug effects; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D051116:Receptors, Scavenger / Q000187:drug effects / Q000502:physiology*
D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; D011804:Quinolines; D051116:Receptors, Scavenger; D009569:Nitric Oxide; C483909:torcetrapib; D052250:Nitric Oxide Synthase Type III