Letter by Nakajima and Saito Regarding Article, “Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits”
To the Editor:
Koike et al1 recently reported in Circulation that the transgenic expression of human C-reactive protein (CRP) in rabbits fed a cholesterol-rich diet did not promote the pathogenesis of atherosclerosis despite its detection in atherosclerotic plaque. This result supports some animal studies cited in the article and several epidemiological studies that indicate no associations between elevated circulating CRP and cardiovascular disease.2 However, in clinical practice, CRP is often elevated in people with excess visceral fat, independent of genetic influences,3 and predisposes them to critical metabolic dysfunctions related to insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome (MetS). Although glucose metabolism in the transgenic rabbit was not fully described, the rabbits are unlikely to have had abnormal glucose metabolism and insulin resistance given the blood parameters reported in the supplemental data. In addition, although the transgenic rabbits were fed a cholesterol-rich diet, the lipoprotein profiles were identical in the transgenic and nontransgenic rabbits, as described by the authors. Elevated levels of very-low-density lipoprotein, a hallmark of dyslipidemia in type 2 diabetes mellitus and MetS, were not found in the lipoprotein analysis of the transgenic rabbits. Prothrombogenic events (eg, increased plasminogen activator inhibitor-1) also play a key role in promoting cardiovascular events, particularly in MetS. Taken together, the overall metabolic features of the human CRP–expressing transgenic rabbit may be markedly different from those observed in subjects with type 2 diabetes mellitus and MetS. Therefore, regardless of whether the source is endogenous or exogenous, elevated CRP may behave quite differently in different environments. Furthermore, as suggested in a previous study,4 the interaction between genetically elevated CRP with atherosclerotic factors may be different from that induced by metabolic abnormalities.
A recent study, the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study,5 showed the benefits of statin therapy for preventing cardiovascular events in subjects with moderately high CRP but normal low-density lipoprotein cholesterol levels. Most subjects in the trial were overweight (median body mass index 28 kg/m2) with mildly increased glycosylated hemoglobin levels (median 5.7% at baseline and 5.8% to 5.9% at 24 months), and approximately 40% of the subjects were initially diagnosed with MetS, which was probably the main cause of the elevated circulating CRP. Thus, in such settings, elevated CRP might contribute to the development and progression of atherothrombogenic and cardiovascular events. Nevertheless, in the trial, aggressive low-density lipoprotein cholesterol lowering per se, rather than reduced CRP, could affect the outcomes of statin therapy.
Indeed, Koike et al1 reported a novel observation that the expression of human CRP and its ability to activate the endogenous complement do not contribute to the atherogenic activity in these transgenic rabbits, which did not reflect commonly observed clinical features in type 2 diabetes mellitus and MetS. Knockout or overexpression of CRP in animal models of type 2 diabetes mellitus or MetS may reach the core of the issue identified in clinical settings and may reveal the clinical implications of elevated CRP as a principal cause of or a mere marker for atherosclerosis and future cardiovascular events.
Koike T, Kitajima S, Yu Y, Nishijima K, Zhang J, Ozaki Y, Morimoto M, Watanabe T, Bhakdi S, Asada Y, Chen YE, Fan J. Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation. 2009; 120: 2088–2094.
Greenfield JR, Samaras K, Jenkins AB, Kelly PJ, Spector TD, Gallimore JR, Pepys MB, Campbell LV. Obesity is an important determinant of baseline serum C-reactive protein concentration in monozygotic twins, independent of genetic influences. Circulation. 2004; 109: 3022–3028.
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359: 2195–2207.