Abstract 320: Cardiovascular Phenotype of PCSK9 Knockout Mice
Proprotein convertase subtisilin kexin type 9 (PCSK9) promotes LDL receptor (LDLR) degradation and its absence confers life-long low LDL-cholesterol, protection against coronary artery disease. Afro-americans patients with nonsense PCSK9 mutations are less prone to hypertension and plasma PCSK9 is weakly associated to blood pressure (BP) in large cohorts. Recent evidences suggest that PCSK9 degrades the VLDLR in the adipose tissue. This receptor has been involved in hypoxia-induced lipotoxicity following myocardial infarction.
Objectives: We aimed at verifying whether PCSK9 affects heart VLDLR content, myocardial function and BP.
Methods: We used PCSK9-/- and PCSK9+/+ mouse littermates (n = 4-6 per group, 3 to 4 month-old males). Two-dimensional LV long-axis and M-mode images were obtained by echocardiography. Mice were also chronically treated with L-NAME (2 mg/kg/d), angiotensin II (minipump, 1 mg/kg/d ) or DOCA-Salt following unilateral nephrectomy.". BP was measured under a 12:12-hour light/dark schedule using a radiotelemetry system or by computerized tail cuff plethysmography.
Results: Hearts from random-fed PCSK9-/- mice didn’t have more VLDLR content (protein and mRNA) than those of PCSK9+/+ mice and had equal TG contents. Fasting (12h) increased myocardial TG contents to the same extent in both genotypes (+ 100%, fed PCSK9++, PCSK9-/- vs fasted PCSK9++, PCSK9-/-: 18±5,4 microg/mg, 18,5± 11 microg/mg vs 36±3,5 microg/mg, 38± 5,1 microg/mg, n=3). Despite a ∼6-fold increase in plasma PCSK9 concentrations compared to C57Bl6J mice, hearts from LDLR knockout mice had equal quantities of VLDLR protein. Injecting (i.v.) 125 μg of hPCSK9 in PCSK9+/+ mice (>300 times the physiological concentration) led to an 83% (p<0.05) decrease in mature VLDLR, in the heart and to a >90% decrease of hepatic LDLR, as measured by western blot 1h after the injection. Thus, supra-physiological concentrations of PCSK9 can acutely degrade the VLDLR in mouse heart. The dimensions of the ventricular cavity and the thickness of the septal and the posterior walls as well as LV systolic and diastolic functions were unchanged in PCSK9-/- mice. In addition, PCSK9-deficiency did not alter either basal BP or the elevated BP in several models of hypertension.
Collectively these results show that PCSK9 deficiency is neutral on blood pressure or myocardium function at a young age in mice. Plasma PCSK9 at physiological or pathophysiological concentrations do not decrease VLDLR content in the heart.
- © 2012 by American Heart Association, Inc.