title: Off-target effects of thrombolytic drugs: apolipoprotein A-I proteolysis by alteplase and tenecteplase.
abstract: The administration of thrombolytic drugs is of proven benefit in a variety of clinical conditions requiring acute revascularization, including acute myocardial infarction (AMI), ischemic stroke, pulmonary embolism, and venous thrombosis. Generated plasmin can degrade non-target proteins, including apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoproteins (HDL). Aim of the present study was to compare the extent of apoA-I proteolytic degradation in AMI patients treated with two thrombolytic drugs, alteplase and the genetically engineered t-PA variant tenecteplase. ApoA-I degradation was evaluated in sera from 38 AMI patients treated with alteplase or tenecteplase. In vitro, apoA-I degradation was tested by incubating control sera or purified HDL with alteplase or tenecteplase at different concentrations (5-100 μg/ml). Treatment with alteplase and tenecteplase results in apoA-I proteolysis; the extent of apoA-I degradation was more pronounced in alteplase-treated patients than in tenecteplase-treated patients. In vitro, the extent of apoA-I proteolysis was higher in alteplase-treated sera than in tenecteplase-treated sera, in the whole drug concentration range. No direct effect of the two thrombolytic agents on apoA-I degradation was observed. In addition to apoA-I, apoA-IV was also degraded by the two thrombolytic agents and again proteolytic degradation was higher with alteplase than tenecteplase. In conclusion, this study indicates that both alteplase and tenecteplase cause plasmin-mediated proteolysis of apoA-I, with alteplase resulting in a greater apoA-I degradation than tenecteplase, potentially causing a transient impairment of HDL atheroprotective functions.
authors.affiliation: Centro Enrica Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Gomaraschi
authors.forename: Alice
authors.initials: A
authors.lastname: Ossoli
authors.forename: Cecilia
authors.initials: C
authors.lastname: Vitali
authors.forename: Silvia
authors.initials: S
authors.lastname: Pozzi
authors.forename: Laura
authors.initials: L
authors.lastname: Vitali Serdoz
authors.forename: Cristina
authors.initials: C
authors.lastname: Pitzorno
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Guido
authors.initials: G
authors.lastname: Franceschini
authors.forename: Laura
authors.initials: L
authors.lastname: Calabresi
mesh_terms: D000368:Aged; D016632:Apolipoprotein A-I / Q000378:metabolism*; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy*; D000077785:Tenecteplase; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D016632:Apolipoprotein A-I; D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase