Response to C-Reactive Protein and Cardiovascular Disease: Differences Between Humans and Mice
We thank Jeppesen and Asferg1 for reading our article2 and making comments. Jeppesen and Asferg1 stated correctly that we concluded that C-reactive protein (CRP) may act not only as an inflammation marker but also as a mediator in hypertensive cardiac remodeling.2 We agree that insights gained from the study of human CRP in a mouse model of hypertension may ultimately prove not so relevant to human hypertension and its complications, but we disagree that the results from the mouse model apply only to the special case of mice. Indeed, the role of CRP in patients with cardiovascular disease remains controversial, because some reports indicate that CRP itself is not causally related to hypertension and its complications in humans as indicated in the Letter to Editor (see References 1, 3, and 4 in Reference 1), whereas other studies clearly demonstrate a close link between elevated levels of CRP and risk for cardiovascular disease as cited in our study (References 12, 13 in Reference 2) and in a most recent large-scale study.3 We recognized this conflict in the available literature; therefore, the exact role of CRP in cardiovascular disease remains largely unknown.2 It was space limitations, not bias, that prevented us from citing more of the “negative” literature.
In a companion study where we investigated the role of human CRP in a CRP transgenic mouse model of obstructive kidney disease, we demonstrated that CRP significantly promotes early development of renal inflammation and fibrosis, yet this action fails to correlate with the advanced renal progression (article in preparation). These new observations may help in explanation of the seemingly paradoxical observations made in the clinical studies. Although our model system (CRP transgenic mice carrying implanted minipumps laden with angiotensin II) does not perfectly replicate the condition exhibited by humans with hypertension, the actions of CRP in hypertensive cardiac remodeling that were revealed in our study are meaningful and may lead to a better understanding of the biological activities of CRP in cardiac inflammation and fibrosis associated with angiotensin II–induced hypertension in general. We are certain the readers of Hypertension will all agree with this and will come to their own conclusion as to whether results from mice are extendable to humans. We would like to take this opportunity to remind the readers that studies done in CRP transgenic mice may address actual CRP biology, whereas observational studies of patients using Mendelian randomization merely model/infer CRP biology. Both approaches have their inherent strengths and weaknesses, and neither is perfect.
In summary, the Letter to the Editor1 is appreciated, because it will serve as a good reminder to the readership of Hypertension that the results of studies conducted using animal models may or may not extrapolate to humans. We hope that our reply is at least of equal merit, as it is a reminder that statistically significant associations do not always reflect cause-and-effect biology. Ultimately, whether human CRP has a pathogenic role in human cardiovascular disease will require randomized controlled trials in patients. Until then, the best-laid scientific plans of CRP transgenic mice and humans will often go awry.
Sources of Funding
This work has been supported by grants from the Research Grant Council of Hong Kong Special Administrative Region (RGC GRF 768409).
Jeppesen J, Asferg C. C-reactive protein and cardiovascular disease: differences between humans and mice. Hypertension. 2010; 56: e15.
Zhang R, Zhang YY, Huang XR, Wu Y, Chung AC, Wu EX, Szalai AJ, Wong BC, Lau CP, Lan HY. C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease. Hypertension. 2010; 55: 953–960.
Park CS, Ihm SH, Yoo KD, Kim DB, Lee JM, Kim HY, Chung WS, Seung KB, Kim JH. Relation between C-reactive protein, homocysteine levels, fibrinogen, and lipoprotein levels and leukocyte and platelet counts, and 10-year risk for cardiovascular disease among healthy adults in the USA. Am J Cardiol. 2010; 105: 1284–1288.