Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man.

Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population-based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.

Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis.

BACKGROUND: Vascular lipid accumulation and inflammation are hallmarks of atherosclerosis and perpetuate atherosclerotic plaque development. Mediators of inflammation, ie, interleukin (IL)-6, are elevated in patients with acute coronary syndromes and may contribute to the exacerbation of atherosclerosis. METHODS AND RESULTS: To assess the role of IL-6 in atherosclerosis, ApoE-/--IL-6-/- double-knockout mice were generated, fed a normal chow diet, and housed for 53+/-4 weeks. Mortality and blood pressure were unaltered. However, serum cholesterol levels and subsequent atherosclerotic lesion formation (oil red O stain) were significantly increased in ApoE-/--IL-6-/- mice compared with ApoE-/-, wild-type (WT), and IL-6-/- mice. Plaques of ApoE-/--IL-6-/- mice showed significantly reduced transcript and protein levels of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, collagen I and V, and lysyl oxidase (by reverse transcriptase-polymerase chain reaction and immunohistochemistry). Recruitment of macrophages and leukocytes (Mac3- and CD45-positive staining) into the atherosclerotic lesion was significantly reduced in ApoE-/--IL-6-/- mice. The transcript and serum protein (ELISA) levels of IL-10 were significantly reduced. CONCLUSIONS: Thus, a lifetime IL-6 deficiency enhances atherosclerotic plaque formation in ApoEK-/--IL-6-/- mice and leads to maladaptive vascular developmental processes. These observations are consistent with the notion that baseline levels of IL-6 are required to modulate lipid homeostasis, vascular remodeling, and plaque inflammation in atherosclerosis.

Combined effects of HMG-CoA-reductase inhibition and renin-angiotensin system blockade on experimental atherosclerosis.

Therapeutic strategies to prevent atherosclerotic plaque progression and achieve plaque stabilization involve 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitors (statins) and renin-angiotensin system (RAS)-blockade, but studies investigating the potentially additive effects of a combined treatment strategy are rare. We hypothesised that the adjunction of atorvastatin with telmisartan or ramipril might achieve additional effects on experimental atherosclerosis though statin-induced lipid-lowering is lacking. ApoE-/- mice were fed a high-fat diet for 12 weeks and randomized to either placebo (CON), atorvastatin (ATO), ramipril (RAM), telmisartan (TEL) or RAM+ATO and TEL+ATO (N=23 per group). RAS-blockade, but not ATO, reduced systolic blood pressure. None of the treatment regimens lowered systemic cholesterol levels or lipoprotein fractions. RAM, TEL and the combined therapy, but not ATO, significantly reduced aortic lipid deposition. All substances significantly reduced monocyte chemoattracting protein (MCP)-1 concentrations, macrophages and matrixmetalloproteinase (MMP)-9 content and enhanced plaque's content of tissue inhibitor of MMP (TIMP)-1, collagen and fibrous cap thickness, resulting in an overall decrease of advanced plaques (classified as types IV-VI). Additive effects of the adjunction were observed on MMP-9 gelatinolytic activity, interleukin (IL)-6 and IL-10 plasma levels. These results indicate that a combined treatment with RAS-blockade and statins may have additive effects on systemic cardiovascular risk markers even in the absence of lipid-reduction, although additional effects on atherosclerotic plaque progression and stability were not observed in this model.

Reviewing peripartum cardiomyopathy: current state of knowledge.

Peripartum cardiomyopathy (PPCM) is a serious, potentially life-threatening heart disease of unknown etiology in previously healthy women that develops between the last month of pregnancy and 5-6 months after delivery. PPCM is a distinct clinical entity in which echocardiography demonstrates the features of an idiopathic dilated cardiomyopathy with a high morbidity and mortality, but in addition, patients suffering with PPCM have a chance of reaching full recovery. A variety of potential risk factors related to PPCM have been suggested over the last decades, which may help to identify women at risk in the future. Recent advances in understanding the pathophysiology of PPCM assign a key role to unbalanced oxidative stress and the generation of a cardiotoxic prolactin subfragment. In this regard, pharmacological blockade of prolactin holds the promise of novel, more disease-specific therapy options. The present article provides an overview on the clinical appearance and management, risk factors and potential pathophysiological mechanisms of PPCM.

Angiotensin II induces MMP-2 in a p47phox-dependent manner.

Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Since reactive oxygen species (ROS) induce MMP-2 and angiotensin II (ANG II) enhances NADPH-oxidase-dependent ROS formation, we assessed whether ANG II induces MMP-2 in a NADPH-oxidase-dependent manner. MMP-2 mRNA expression and activity were analyzed in wildtype and p47phox-deficient (p47phox-/-) murine smooth muscle cells (SMC). To address a clinical implication, sections of human atherosclerotic arteries were stained for MMP-2, p47phox, ANG II, AT1-receptor, and alpha-smooth muscle cell actin (alpha-SMC actin). MMP-2 protein expression and activity from these arteries were compared to those without atherosclerosis. ANG II enhances mRNA synthesis and activity of MMP-2 in a p47phox-dependent manner. Immunohistochemical analyses revealed a co-localization of MMP-2 with p47phox, ANG II, AT1-receptor, and alpha-SMC actin. MMP-2 protein expression and gelatinolytic activity are increased in atherosclerotic arteries. Thus, activation of the renin-angiotensin system may contribute to plaque destabilization via ROS-dependent induction of MMP-2.