The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol ...biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.
Hypercholesterolemia is a major risk factor for cardiovascular diseases, increasing the incidence of myocardial infarction and death. Statin-induced lowering of low-density lipoprotein cholesterol ...(LDL-C) reduces cardiovascular morbidity and mortality. However, many individuals treated with statins do not achieve their target levels of LDL-C, and thus, LDL-associated residual risk remains. Gain-of-function mutations of the proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with hypercholesterolemia and increased risk of cardiovascular events. Conversely, loss-of-function mutations are linked to low plasma LDL-C levels and a reduction of cardiovascular risk without known unwanted effects on individual health. Experimental studies have revealed that PCSK9 reduces the hepatic uptake of LDL-C by increasing the endosomal and lysosomal degradation of LDL receptors (LDLR). Low intracellular cholesterol levels in response to statin treatment activate the sterol regulatory element-binding protein-2 (SREBP-2), resulting in coexpression of LDLR and PCSK9. Although this self-regulatory mechanism contributes to maintain cholesterol homeostasis preventing excessive cholesterol uptake, it may limit the therapeutic effect of statins. A number of clinical studies have demonstrated that inhibition of PCSK9 alone and in addition to statins potently reduces serum LDL-C concentrations. Moreover, experimental studies indicate that PCSK9 might accelerate atherosclerosis by promoting inflammation, endothelial dysfunction, and hypertension by mechanisms independent of the LDLR. Further research is needed to characterize the potential therapeutic and to rule out unwanted off-target effects of PCSK9 inhibition. In this review we elucidate the role of PCSK9 in lipid homeostasis, highlight the impact of PCSK9 on atherosclerosis, and summarize current therapeutic strategies targeting PCSK9.
Clinical review on triglycerides Laufs, Ulrich; Parhofer, Klaus G; Ginsberg, Henry N ...
European heart journal,
01/2020, Volume:
41, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
Hypertriglyceridaemia is a common clinical problem. Epidemiologic and genetic studies have established that triglyceride-rich lipoproteins (TRL) and their remnants as important contributors ...to ASCVD while severe hypertriglyceridaemia raises risk of pancreatitis. While low-density lipoprotein is the primary treatment target for lipid lowering therapy, secondary targets that reflect the contribution of TRL such as apoB and non-HDL-C are recommended in the current guidelines. Reduction of severely elevated triglycerides is important to avert or reduce the risk of pancreatitis. Here we discuss interventions for hypertriglyceridaemia, including diet and lifestyle, established treatments such as fibrates and omega-3 fatty acid preparations and emerging therapies, including various biological agents.
Increased hepatocyte death contributes to the pathology of acute and chronic liver diseases. However, the role of hepatocyte pyroptosis and extracellular inflammasome release in liver disease is ...unknown.
We used primary mouse and human hepatocytes, hepatocyte-specific leucine 351 to proline Nlrp3KICreA mice, and GsdmdKO mice to investigate pyroptotic cell death in hepatocytes and its impact on liver inflammation and damage. Extracellular NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes were isolated from mutant NLRP3-YFP HEK cells and internalisation was studied in LX2 and primary human hepatic stellate cells. We also examined a cohort of 154 adult patients with biopsy-proven non-alcoholic fatty liver disease (Sir Charles Gairdner Hospital, Nedlands, Western Australia).
We demonstrated that primary mouse and human hepatocytes can undergo pyroptosis upon NLRP3 inflammasome activation with subsequent release of NLRP3 inflammasome proteins that amplify and perpetuate inflammasome-driven fibrogenesis. Pyroptosis was inhibited by blocking caspase-1 and gasdermin D activation. The activated form of caspase-1 was detected in the livers and in serum from patients with non-alcoholic steatohepatitis and correlated with disease severity. Nlrp3KICreA mice showed spontaneous liver fibrosis under normal chow diet, and increased sensitivity to liver damage and inflammation after treatment with low dose lipopolysaccharide. Mechanistically, hepatic stellate cells engulfed extracellular NLRP3 inflammasome particles leading to increased IL-1β secretion and α-smooth muscle actin expression. This effect was abrogated when cells were pre-treated with the endocytosis inhibitor cytochalasin B.
These results identify hepatocyte pyroptosis and release of inflammasome components as a novel mechanism to propagate liver injury and liver fibrosis development.
Our findings identify a novel mechanism of inflammation in the liver. Experiments in cell cultures, mice, and human samples show that a specific form of cell death, called pyroptosis, leads to the release of complex inflammatory particles, the NLRP3 inflammasome, from inside hepatocytes into the extracellular space. From there they are taken up by other cells and thereby mediate inflammatory and pro-fibrogenic stress signals. The discovery of this mechanism may lead to novel treatments for chronic liver diseases in the future.
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•Human and murine hepatocytes undergo pyroptosis and release NLRP3 inflammasome proteins.•Pyroptotic cell death in hepatocytes is dependent on caspase-1 and gasdermin D activation.•Caspase-1 activity is increased in livers and serum from NASH patients.•Nlrp3KICreA mice develop fibrosis and show increased sensitivity to liver damage.•Human hepatic stellate cells internalise extracellular NLRP3-YFP oligomeric particles.•Extracellular NLRP3 oligomeric particles perpetuate inflammation and fibrogenesis.
Pleiotropic effects of statins LIAO, James K; LAUFS, Ulrich
Annual review of pharmacology and toxicology,
01/2005, Volume:
45, Issue:
1
Journal Article
Peer reviewed
Open access
Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits ...observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.
Histamine exerts cAMP-dependent positive inotropic effects (PIE) and positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic mice which overexpress the human ...H
2
-receptor in the heart (=H
2
-TG). To determine whether these effects are antagonized by phosphodiesterases (PDEs), contractile studies were done in isolated left and right atrial preparations of H
2
-TG. The contractile effects of histamine were tested in the additional presence of the PDE-inhibitors
erythro
-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA, 1 μM, PDE2-inhibitor) or cilostamide (1 μM, PDE3-inhibitor), rolipram (10 μM, a PDE4-inhibitor), and their combinations. Cilostamide (1 μM) and EHNA (1 μM), rolipram (1 μM), and EHNA (1 μM) and the combination of rolipram (0.1 μM) and cilostamide (1 μM) each increased the potency of histamine to elevate the force of contraction (FOC) in H
2
-TG. Cilostamide (1 μM) and rolipram (10 μM) alone increased and EHNA (1 μM) decreased alone, and their combination increased the potency of histamine to increase the FOC in H
2
-TG indicating that PDE3 and PDE4 regulate the inotropic effects of histamine in H
2
-TG. The PDE inhibitors (EHNA, cilostamide, rolipram) alone did not alter the potency of histamine to increase the heart beat in H
2
-TG whereas a combination of rolipram, cilostamide, and EHNA, or of rolipram and EHNA increased the potency of histamine to act on the beating rate. In summary, the data suggest that the PCE of histamine in H
2
-TG atrium involves PDE 2 and 4 activities, whereas the PIE of histamine are diminished by activity of PDE 3 and 4.
Chronic heart failure (CHF) is one of the leading causes of hospitalization, morbidity, and mortality worldwide. This review summarizes current knowledge with regard to CHF as a risk factor for ...ischemic stroke. CHF is associated with an increased risk of thrombus formation and is accompanied by a 2- to 3-fold increased risk of stroke. Moreover, stroke in CHF patients is associated with poor outcome and higher mortality. Available evidence for additional "vascular" stroke risk factors in heart failure patients is inconsistent and is mostly derived from cohort studies or retrospective analyses. Current guidelines recommend anticoagulation for CHF patients with concomitant atrial fibrillation but not for those in sinus rhythm. Prospective studies are needed to test whether early detection and optimal treatment of CHF reduces the burden of stroke-associated neurologic and neuropsychological sequelae.
In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds ...to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in
exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in
are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2-4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of ∼46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available.
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