Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

Abstract

The association between circulating concentrations of C-reactive protein (CRP) and future atherothrombotic events has provoked speculation about a possible pathogenetic role of CRP. However, we show here that transgenic expression of human CRP had no effect on development, progression, or severity of spontaneous atherosclerosis, or on morbidity or mortality, in male apolipoprotein E (apoE)-deficient C57BL͞6 mice up to 56 weeks, despite deposition of human CRP and mouse complement component 3 in the plaques. Although female apoE knockouts develop atherosclerosis more rapidly than males, the human CRP transgene is under sex hormone control and is expressed at human levels only in males. We therefore studied only male mice. The concentration of mouse serum amyloid P component, an extremely sensitive systemic marker of inflammation, remained normal throughout except for transient spikes in response to fighting in a few animals, indicating that atherogenesis in this model is not associated with an acute-phase response. However, among human CRP transgenic mice, the circulating CRP concentration was higher in apoE knockouts than in wild-type controls. The higher CRP values were associated with substantially lower estradiol concentrations in the apoE-deficient animals. Human CRP transgene expression is thus up-regulated in apoE-deficient mice, apparently reflecting altered estrogen levels, despite the absence of other systemic signs of inflammation. Extrapolation to human pathology from this xenogeneic combination of human CRP with apoE deficiency-mediated mouse atherosclerosis must be guarded. Nevertheless, the present results do not suggest that human CRP is either proatherogenic or atheroprotective in vivo.atherosclerosis ͉ inflammation ͉ transgenic

Neointimal formation is reduced after arterial injury in human crp transgenic mice

“…High CRP levels are predictive of acute cardiovascular events and of worse outcome following myocardial infarction and percutaneous coronary interventions, but do not correlate with the burden of atherosclerosis [16,17]. In a transgenic mouse model human CRP clearly predisposed to thrombosis [3], but most reports do not support a causal role in atherogenesis [18][19][20][21]. The present study examined the effect of CRP on vascular repair following wire injury in the femoral artery of CRP transgenic mice in which thrombosis was pharmacologically suppressed.…”

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

“…Conflicting results have been generated using these mice, some investigators have reported activation of complement, accelerated atherosclerosis and increased expression of angiotensin receptor-1, vascular cell adhesion molecule and collagen [68]. In contrast using the same murine model other investigators neither reported proinflammatory nor proatherogenic effects [69].…”

C-Reactive Protein in Estimating Inflammatory Status in Patients with Acute Coronary Syndrome

“…It cannot be, of course, concluded from these results whether CRP levels are triggers or just indicators of cardiovascular events, and results from in vitro experiments and animal models are controversial (18)(19)(20)(21). However, ongoing works show that specific inhibitors of CRP, such as 1,6-bis(phosphocholin)-hexane, can be beneficial in the treatment of cardiovascular diseases (22).…”