Mark C. Kowala

Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyses the rate limiting step in cholesterol biosynthesis and is markedly inhibited by the statin family of drugs. The effect of statins on lipid lowering is clearly defined, but the ability of the drugs to directly regulate inflammatory functions has not been well explored. In this report, we show that there are differences among the statins in their capacity to induce proinflammatory responses both in human monocytes in vitro, and in leukocytes in mice in vivo. Treatment of human monocytes with lipophilic statins alone stimulated the production of MCP-1, IL-8, TNF-alpha and IL-1 beta and markedly sensitized the cells to subsequent challenge with inflammatory agents. Lipophilic statins also increased the production of reactive oxygen species in monocytes. In contrast, pretreatment of cells with the hydrophilic pravastatin did not induce these heightened inflammatory responses. Furthermore, treatment of mice with lipophilic statins caused a markedly higher influx of leukocytes into the inflamed peritoneal cavity following challenge with thioglycollate. Overall, these results demonstrate that the lipophilic statins influence a regulatory pathway in monocytes that controls cytokine production and that the statins induce different pro-inflammatory responses both in vitro and in vivo.

Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophage—foam cell accumulation independently of blood pressure and plasma lipids

The effect of two angiotensin converting enzyme (ACE) inhibitors on the development of atherosclerosis was determined in hyperlipidemic hamsters. Preliminary studies indicated that only fosinopril (50 mg/kg) temporarily decreased mean arterial pressure, while after chronic dosing fosinopril and captopril (50 mg/kg) were ineffective. The same dose of fosinopril and captopril inhibited the angiotensin I pressor response, indicating these agents suppressed ACE activity in vivo. In the 3 week atherosclerosis experiment, all hamsters were fed chow supplemented with 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with those receiving either 50 mg/kg per day of fosinopril or 50 mg/kg per day of captopril. After 3 weeks, fosinopril reduced plasma total cholesterol, low density lipoprotein (LDL) plus very low density lipoprotein cholesterol and total triglycerides by 17%, 27% and 45%, respectively. Captopril only reduced high density lipoprotein cholesterol by 20%. Neither fosinopril or captopril altered blood pressure at 3 weeks. Atherosclerosis was quantified from en face preparations of the lesion-prone aortic arch that were stained with oil red O (for cholesteryl ester and triglycerides). In control hamsters, oil red O labeled numerous subendothelial macrophage-foam cells located along the inner curvature of the aortic arch. Compared with controls, fosinopril reduced the number of intimal macrophage-foam cells/mm2, foam cell size and the fatty streak area by 85%, 38% and 90%, respectively. Captopril decreased these parameters by 44%, 16% and 53%. Thus captopril decreased early atherosclerosis without affecting plasma LDL cholesterol or blood pressure, which suggested that inhibiting ACE (or kininase II) directly impeded the accumulation and formation of macrophage-foam cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of atherosclerosis in LDL receptor knockout mice: macrophage accumulation correlates with rapid and sustained expression of aortic MCP-1/JE.

Atherosclerosis and the expression of monocyte chemoattractant protein-1 (MCP-1) were quantified in low density lipoprotein receptor knockout (LDLR KO) mice fed 1.25% cholesterol (study #1) or 0.2% cholesterol (study #2). In study #1 plasma total cholesterols leveled-off at 1800 mg/dl whereas plasma triglycerides remained low. In en face specimens of the aortic root and arch, intimal foam cells plus extracellular lipid particles accumulated and by 8 weeks the fatty streak surface area had rapidly expanded at both sites. In study #2, total cholesterols averaged 400 mg/dl and fatty streaks were 2-3-fold smaller compared to those in study #1. In study #3, LDLR KO mice were fed chow or 1.25% cholesterol, and immunostaining demonstrated a few Mac-2-positive intimal macrophages in mice fed chow, and during the first 10 weeks of hypercholesterolemia the number of intimal macrophages increased continuously. In chow-fed mice (0 weeks) there was little MCP-1 in the aorta. After 2 days of hypercholesterolemia intimal macrophages stained for MCP-1, and during the next 10 weeks recently recruited arterial macrophages also expressed MCP-1. Macrophage accumulation was highly correlated with MCP-1 expression. In study #4, feeding LDLR KO mice 1.25% cholesterol for 6 months produced atherosclerotic plaques at both sites and they contained a fibrous cap of smooth muscle cells, macrophage-foam cells, connective tissue and cholesterol crystals. In summary, LDLR KO mice fed cholesterol develop fatty streaks that transform into fibrous plaques. Hypercholesterolemia rapidly triggers MCP-1 expression in resident intimal macrophages, which is followed by the accumulation of more macrophages that also express MCP-1, suggesting that this chemokine may both initiate and amplify monocyte recruitment to the artery wall during early atherogenesis.

The role of endothelin in the pathogenesis of atherosclerosis.

Publisher Summary Atherosclerosis is a chronic inflammatory response triggered by the continuous accumulation of arterial low density lipoprotein (LDL). The developing fibrous cap of the atheroma is comparable to the growth of scar tissue following sublethal injury. Recent research indicates that endothelin (ET) may participate in such vascular diseases. ET and its receptors are localized in endothelial cells, macrophages, and smooth muscle cells of atherosclerotic and arteriosclerotic lesions and also in the same cells isolated in vitro . ET receptor antagonists retard the accumulation of intimal smooth muscle cells after balloon injury and decreased arterial macrophage foam cell number and size during hyperlipidemia. Therefore, blocking the effects of ET with receptor antagonists diminishes the progression of vascular diseases in vivo . Further evidence for ET involvement in atherogenesis has been obtained from atherectomy specimens of human atherosclerotic plaques that have an increased expression of mRNA for preproendothelin, and ET-1-like immunoreactivity has been detected in vascular smooth muscle. This chapter summarizes and interprets pertinent information supporting this concept, but first briefly describes the pathogenesis of atherosclerosis to provide a context for the role of ET in this disease process.

Chapter 7. Advances in the understanding and treatment of congestive heart failure (HF)

Publisher Summary This chapter focuses on advances in the understanding and treatment of congestive heart failure (HF). HF is a chronic, expensive, and fatal disease. It occurs when cardiac output fails to meet end organ needs for blood flow. Many different classes of drugs are used in the treatment of HF with varied results. The disease is best treated with several drugs of multiple actions, but the exact combination of agents is an ever shifting landscape. Congestive heart failure is one of the single largest causes of death in industrialized countries. The severe syndrome of congestive heart failure involves shortness of breath (dyspenia), pulmonary edema, pulmonary hypertension and edema in the periphery. The chapter summarizes the major physiological and biochemical mechanisms of heart failure that current drug therapies modify. Included in the discussion are descriptions of the drugs used to treat HF, recent clinical trials with those drugs, and new molecular entities into the different classes of drugs. Novel, untested molecules and approaches to the treatment of congestive heart failure are also discussed.