Neprilysin Inhibitor–Angiotensin II Receptor Blocker Combination Therapy (Sacubitril/valsartan) Suppresses Atherosclerotic Plaque Formation and Inhibits Inflammation in Apolipoprotein E- Deficient Mice

Abstract

We assessed the effects of the sacubitril/valsartan combination drug (LCZ696), in comparison to valsartan alone, on the progression of atherosclerotic plaque formation and inflammatory gene expression in apolipoprotein E- deficient mice (apoE −/− mice). Seventy-two apoE −/− mice were fed a western diet and a constrictive silastic tube was used to elicit carotid lesion formation. The animals were separated into a control group, a valsartan group or an LCZ696 group (n = 24 in each group). Plaques in the carotid artery were harvested 12 weeks later for histological examination. The levels of pro-inflammatory genes in the plasma and lesions were detected using real-time PCR and ELISA. Valsartan or LCZ696 treatment remarkably inhibited the expression of pro-inflammatory genes, including interleukin-6, matrix metalloproteinase-8 and monocyte chemotactic protein-1, in comparison with the control group. Meanwhile, both valsartan and LCZ696 suppressed the formation of atherosclerotic plaques by decreasing plaque lipid content and cross-sectional plaque area and increasing the content of plaque collagen and fibrous cap thickness. In particular, LCZ696 performed the best in suppressing atherosclerosis and inhibiting the level of pro-inflammatory genes. LCZ696 significantly ameliorated atherosclerosis and inflammation in apoE −/− mice compared with valsartan.

The Cross-Talk between Age, Hypertension and Inflammation in COVID-19 Patients: Therapeutic Targets

“…Sacubitril/valsartan reduced the concentration of proinflammatory cytokines and neutrophil count, while increasing lymphocyte count more than valsartan alone or placebo [ 61 ].…”

Mechanisms of Myocardial Injury in Coronavirus Disease 2019

“…This finding might be related to the increase in plasma levels of atrial/brain/C-type natriuretic peptide, Ang I/II, substance P, bradykinin and endothelin secondary to neprilisin inhibition by sacubitril. 46 Therefore, administration of an ACE, an ARB or sacubitril/valsartan may even be beneficial through inhibition of AT1R. 47…”

Management of sacubitril/valsartan combination in an end-stage heart failure patient hospitalized for COVID-19 pneumonia: Should we withdraw temporarily or continue?

“…Anti-inflammatory effect mainly driven by the protection of lymphocyte count may be an important feature of sacubitril in patients with chronic heart failure. As an additional clinical effect, early administration of neprilysin inhibitor in decompensated heart failure may also result in a decrease in high sensitive C-reactive protein (hs-CRP) levels (9). In our case, we detected an increase in lymphocyte count and a relative decrease in hs-CRP level at the end of the first week after hospitalization.…”

“…Previous studies demonstrated an increment in lymphocyte counts in heart failure patients treated by neprilysin inhibitor (9,10). Anti-inflammatory effect mainly driven by the protection of lymphocyte count may be an important feature of sacubitril in patients with chronic heart failure.…”