Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model

Abstract

Arterial inflammatory responses are thought to be a significant component of atherosclerotic disease. We describe here, using a transgenic approach, the mutual perpetuation of immune-mediated arterial inflammation and cholesterol-induced atherosclerosis. Mice expressing the bacterial transgene ␤-galactosidase exclusively in cardiomyocytes and in smooth muscle cells in lung arteries and the aorta (SM-LacZ), and hypercholesterolemic apolipoprotein E-deficient SM-LacZ mice (SM-LacZ͞apoE ؊/؊ ) developed myocarditis and arteritis after immunization with dendritic cells presenting a ␤-galactosidase-derived immunogenic peptide. Hypercholesterolemia amplified acute arteritis and perpetuated chronic arterial inflammation in SM-LacZ͞apoE ؊/؊ mice, but had no major impact on acute myocarditis or the subsequent development of dilated cardiomyopathy. Conversely, arteritis significantly accelerated cholesterol-induced atherosclerosis. Taken together, these data demonstrate that the linkage of immune-mediated arteritis and hypercholesterolemia favors initiation and maintenance of atherosclerotic lesion formation. Therapeutic strategies to prevent or disrupt such self-perpetuating vicious circles may be crucial for the successful treatment of atherosclerosis.

Oxidized Low-Density Lipoprotein Promotes Mature Dendritic Cell Transition from Differentiating Monocyte

“…Most of the clinical events have been attributed to the arterial inflammatory responses initiated by the oxidation of LDL trapped in the extracellular space. Ludewig et al (50) have shown that hypercholesterolemia, a high level of LDL associated with elevated oxLDL production, is a predisposing factor for inflammation and immunity in the vascular wall, and it contributes to the establishment of a chronic inflammatory state.…”

Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice

“…Transgenic SM-LacZ mice expressing β-gal under the control of the smooth muscle-specific protein SM22 promoter have been described (49). ApoE -/-mice were crossed with SM-LacZ mice, and heterozygous offspring were mated to produce ApoE-deficient mice expressing β-gal in arterial SMCs as described previously (8,50). ROSA26/ApoE -/-, SM-LacZ, and SM-LacZ/ApoE -/-mice were bred in our laboratory.…”

β3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice

“…This observation is unexpected but not unprecedented. Dietary cholesterol accelerates pulmonary inflammation in a mouse model of asthma (29), and lipid levels may modulate several limbs of the inflammatory response (30)(31)(32). Previous data suggest a role for integrins in the suppression of pulmonary inflammation.…”

“…Smooth muscle cells contain the greatest mass of ␣v␤3 in the normal vasculature. Arterial smooth muscle cell inflammation promotes intimal proliferation and foam cell formation in the setting of dietary hypercholesterolemia (32).…”