PCSK9 inhibitor improves cardiac function and reduces infarct size in rats with ischaemia/reperfusion injury: Benefits beyond lipid-lowering effects.

During acute cardiac ischaemia/reperfusion (I/R), an increased plasma proprotein convertase subtilisin/kexin 9 (PCSK9) level instigates inflammatory and oxidative processes within ventricular myocytes, resulting in cardiac dysfunction. Therefore, PCSK9 inhibitor (PCSK9i) might exert cardioprotection against I/R injury. However, the effects of PCSK9i on the heart during I/R injury have not been investigated. The effects of PCSK9i given at different time-points during I/R injury on left ventricular (LV) function were investigated. Male Wistar rats were subjected to cardiac I/R injury and divided into 3 treatment groups (n = 10/group): pre-ischaemia, during ischaemia and upon onset of reperfusion. The treatment groups received PCSK9i (Pep2-8, 10 µg/kg) intravenously. A control group (n = 10) received saline solution. During the I/R protocol, arrhythmia scores and LV function were determined. Then, the infarct size, mitochondrial function, mitochondrial dynamics and level of apoptosis were determined. PCSK9i given prior to ischaemia exerted cardioprotection through protection of cardiac mitochondrial function, decreased infarct size and improved LV function, compared with control. PCSK9i administered during ischaemia and upon the onset of reperfusion did not provide any of those benefits. PCSK9i administered before ischaemia exerts cardioprotection, as demonstrated by the attenuation of infarct size and cardiac arrhythmia during cardiac I/R injury. The attenuation is associated with improved mitochondrial function and connexin43 phosphorylation, leading to improved LV function.

Pretreatment With PCSK9 Inhibitor Protects the Brain Against Cardiac Ischemia/Reperfusion Injury Through a Reduction of Neuronal Inflammation and Amyloid Beta Aggregation.

Background Cardiac ischemic/reperfusion (I/R) injury leads to brain damage. A new antihyperlipidemic drug is aimed at inhibiting PCSK 9 (proprotein convertase subtilisin/kexin type 9), a molecule first identified in a neuronal apoptosis paradigm. Thus, the PCSK 9 inhibitor ( PCSK 9i) may play a role in neuronal recovery following cardiac I/R insults. We hypothesize that PCSK 9i attenuates brain damage caused by cardiac I/R via diminishing microglial/astrocytic hyperactivation, ß-amyloid aggregation, and loss of dendritic spine. Methods and Results Adult male rats were divided into 7 groups: (1) control (n=4); (2) PCSK 9i without cardiac I/R (n=4); (3) sham (n=4); and cardiac I/R (n=40). Cardiac I/R rats were divided into 4 subgroups (n=10/subgroup): (1) vehicle; (2) PCSK 9i (10 µg/kg, IV) before ischemia; (3) PCSK 9i during ischemia; and (4) PCSK 9i at the onset of reperfusion. At the end of cardiac I/R protocol, brains were removed to determine microglial and astrocytic activities, ß-amyloid aggravation, and dendritic spine density. The cardiac I/R led to the activation of the brain's innate immunity resulting in increasing Iba1+ microglia, GFAP + astrocytes, and CD 11b+/ CD 45+high cell numbers. However, CD 11b+/ CD 45+low cell numbers were decreased following cardiac I/R. In addition, cardiac I/R led to reduced dendritic spine density, and increased ß-amyloid aggregation. Only the administration of PCSK 9i before ischemia effectively attenuated these deleterious effects on the brain following cardiac I/R. PCSK 9i administration under the physiologic condition did not affect the aforementioned parameters. Conclusions Cardiac I/R injury activated microglial activity in the brain, leading to brain damage. Only the pretreatment with PCSK 9i prevented dendritic spine loss via reduction of microglial activation and Aß aggregation.

The effects of proprotein convertase subtilisin/kexin type 9 inhibitors on lipid metabolism and cardiovascular function.

Low density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease. Although there are several developed lipid lowering drugs such as statins and fenofibrates, many patients do not achieve an adequate response. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been developed as a new therapeutic strategy for cholesterol regulation. PCSK9 binds to low density lipoprotein receptors (LDLR) and initiates LDLR degradation, elevating LDL-C. Therefore, PCSK9 inhibition could exert beneficial effects on cardiovascular disease outcomes. This review comprehensively summarizes and discusses the effects of PCSK9 inhibitors on lipid metabolism and cardiovascular function comparatively with current lipid lowering drugs. This review also details essential information regarding the cardiovascular benefits of PCSK9 inhibition which could encourage further clinical studies.