Abstract
SummaryMolecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E−/− [ApoE−/−] and LDL receptor−/− [Ldlr−/−] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE−/− and Ldlr−/− mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE−/− strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE−/− mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.
Highlights
Atherosclerosis-associated cardiovascular disease (CVD) remains the leading cause of mortality in the Western society and most other parts of the world (Libby et al, 2011; Maseri et al, 2011)
Cold Exposure Activates brown adipose tissue (BAT) and Induces brown-like adipose tissue (BRITE) To study the effect of low temperature on alterations of both white adipose tissue (WAT) and BAT in ApoEÀ/À mice, 8-week-old adult animals that were fed with a high-fat diet (HFD) for 4 weeks were divided into 2 groups (n = 20/group)
Histological analysis of subcutaneous WAT (sWAT) showed that the average size of the adipocytes was markedly smaller in the cold-exposed group as compared with those exposed to the thermoneutral temperature (Figures 1A and 1B)
Summary
Atherosclerosis-associated cardiovascular disease (CVD) remains the leading cause of mortality in the Western society and most other parts of the world (Libby et al, 2011; Maseri et al, 2011). Abundant evidence from epidemiological studies has linked cardiovascular disorders to the cold seasons or low ambient temperature (The Eurowinter Group, 1997; Barnett, 2007; Basu et al, 2005; Braga et al, 2001; Morabito et al, 2005; Wolf et al, 2009) Despite this long-known linkage between cold and high CVD risk, mechanisms underlying cold-induced CVD remain poorly understood, snow removal during the winter season has been claimed to be associated with increased CVD incidence (Franklin et al, 2001; Janardhanan et al, 2010). Cold-triggered high metabolic rates may alter plasma lipid profiles, leading to accelerated development and progression of metabolically related disorders, such as atherosclerosis and diabetes, if an individual already suffers from this type of disorder. Deletion of apolipoprotein E (ApoE) and lowdensity lipoprotein receptor (Ldlr) in mice leads to development of atherosclerotic lesions in the aorta and its branches, due to
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