sacubitril and Inflammation

Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS).. Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001).. Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.

Topics: Aminobutyrates; Animals; Apoptosis; Biphenyl Compounds; Cardio-Renal Syndrome; Cardiovascular Agents; Drug Combinations; Fibrosis; Humans; Inflammation; Kidney; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Simendan; Stroke Volume; Valsartan; Ventricular Function, Left

In ischemia/reperfusion (I/R) injury, both inflammation and apoptosis play a vital role, and the inhibition of excessive inflammation and apoptosis show substantial clinical potential in the treatment of I/R disease. The role of sacubitril/valsartan (SAC/VAL)-a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI)-in inflammation regulation and apoptosis in the context of I/R injury needs to be further explored. In this study, we investigate the short- and long-term effects of SAC/VAL administration in treating adult murine I/R injury both in vivo and in vitro. Our results verified that the application of SAC/VAL could reduce infarct size and suppress apoptosis and the inflammatory response in the acute phase post I/R. Long-term application of SAC/VAL for four weeks significantly improved ventricular function and reversed pathological ventricular remodeling. Mechanistically, SAC/VAL treatment induces the inhibition of the GSK3β-mediated NF-κB pathway through synergistically blocking angiotensin 1 receptor (AT1R) and activating natriuretic peptide receptor (NPR). In summary, we reported the therapeutic role of SAC/VAL in regulating the GSK3β/NF-κB signaling pathway to suppress the inflammatory response and apoptosis, thereby reducing cardiac dysfunction and remodeling post I/R.

Topics: Angiotensins; Animals; Glycogen Synthase Kinase 3 beta; Inflammation; Mice; Myocardial Reperfusion Injury; Myocytes, Cardiac; Neprilysin; NF-kappa B; Receptors, Angiotensin; Tetrazoles; Valsartan

Doxorubicin (DOX) is a well-known cardiotoxic agent, whereas sacubitril/valsartan (Sac/Val) is an effective treatment option in heart failure. In this study, we aimed to evaluate the effect of Sac/Val on DOX-induced cardiotoxicity in pretreatment mice model.. A total of 24 mice were equally classified into 4 groups; control group, DOX (20 mg/kg; fifth day), Sac/Val (80 mg/kg), and Sac/Val+DOX (Sac/Val was given from day one of the study before doxorubicin administration). Electrocardiography parameters, including durations of QRS, ST, QT, PP segment, and QT/PQ index were measured. Total antioxidant status (TAS), total oxidant status (TOS), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, NT-proBNP concentrations, and Caspase 3 activity were evaluated.. At the end of the 9-day study duration, QRS, ST, QT intervals, QT/PQ index and TAS, TOS, TNF-α, IL-1β, IL-6 levels were significantly higher in the DOX group than in the control group (p<0.001). Moreover, there were significant differences only in the PP interval when comparing the Sac/Val+DOX and control groups (p<0.001). QRS, ST, QT intervals, and QT/PQ index, TAS, TOS, TNF-α, IL-1β, IL-6 levels were significantly lower in the Sac/Val+ DOX group compared with the DOX group (p<0.001). Furthermore, NT-proBNP levels were lower in the Sac/Val+DOX group compared with the DOX group along with less Caspase 3 apoptosis.. Sac/Val seems to be cardioprotective against DOX-induced cardiotoxicity in pretreatment mice model. These findings can be attributed to the antiarrhythmic, anti-inflammatory, antioxidant, and antiapoptotic effects of Sac/Val as shown in this study.

Topics: Aminobutyrates; Angiotensins; Animals; Biphenyl Compounds; Cardiotoxicity; Caspase 3; Doxorubicin; Inflammation; Mice; Neprilysin; Oxidative Stress; Receptors, Angiotensin; Valsartan