Modifying Epicardial PCSK9 Expression to Protect Cardiac Function?

Objectives: The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates the levels of LDL receptor (LDL-R). Patients with loss-of-function mutations in the PCSK9 gene show higher levels of the LDL-R, reduced LDL, and protection against cardiovascular disease. PCSK9 inhibitors are a new class of LDL-lowering drugs. PCSK9 is mainly synthesized in the liver. However, adipose tissue (AT) also shows high PCSK9 expression, while PCSK9 is low in cardiac tissue.

Methods: Blood and tissue samples from CABG patients (n = 64) were investigated for PCSK9 release or expression. Adipocytes from patients or mice were stimulated with various compounds and examined concerning PCSK9 expression. Exogenous PCSK9 was utilized to stimulated adult cardiomyocytes or adipocytes.

Results: Human epicardial AT shows a strong PCSK9 mRNA and protein expression which mainly originates from epicardial adipocytes and pre-adipocytes. Interestingly, PCSK9 plasma levels in the coronary sinus are significantly higher than in the peripheral veins, suggesting cardiac PCSK9 release. Furthermore, young normal-weight patients show lowest while old obese patients, which are characterized by typical adipocytokine profiles (high leptin, low adiponectin, high inflammatory mediators such as TNF-alpha), show highest PCSK9 plasma levels. This effect is even more pronounced for PCSK9 mRNA/protein expression in epicardial AT as well as in isolated human adipocytes from these patients. No difference in PCSK9 expression was observed in right atrial tissue. Treatment of human epicardial adipocytes with leptin or TNF-alpha results in a strong increase in PCSK9 expression and release while adiponectin induces a reduction. Inhibition of the AMP-dependent protein kinase (AMPK) prevents the effect of adiponectin. Accordingly, adipocytes from alpha2-AMPK knockout mice show a higher basal PCSK9 expression, and the effects of adiponectin are lacking. Recombinant PCSK9 reduces AMPK-activation in response to adiponectin in these cells and impairs adiponectin-induced effects on metabolism including stimulation of mitochondrial biogenesis, fatty acid uptake or oxidation.

Conclusion: Obese patients with high leptin but low adiponectin show high PCSK9 plasma levels and PCSK9 expression in AT. PCSK9 impairs major metabolic effects of the cardioprotective adipocytokine adiponectin. Epicardial AT may mediate significant metabolic effects in the heart via PCSK9 release. Modification may protect cardiac function.