Targeting C-reactive protein for the treatment of cardiovascular disease

Abstract

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.

Systemic serum amyloid A as a biomarker for exposure to zinc and/or copper-containing metal fumes

“…8,39,40 Whether CRP also has a causal relationship to cardiovascular diseases, is under debate. 8,41,42 In contrast to CRP, SAA is more often discussed as causal factor for cardiovascular disease. 15,16,43 Furthermore, SAA exhibits pro-inflammatory characteristics such as the attraction of phagocytes, the induction of proinflammatory cytokines and the delay of neutrophil apoptosis, 11,12 which may contribute to the pathogenesis of atherosclerosis.…”

Evaluation of the prognostic value of systemic inflammation and socioeconomic deprivation in patients with resectable colorectal liver metastases

“…A myriad of agents targeting varied facets of the innate immune system, including chemokine, interleukin-6 and tumour necrosis factor antagonists, are already in clinical trial. 7 Furthermore, it is now established that CRP plays a direct role in malignant progression 57 and is itself a valid therapeutic target, 58 with several small molecule inhibitors in development. Future studies must define the interplay between the varied facets of the inflammatory response, including the role of particular leucocyte subtypes and cellular products, to enable the rational design and allocation of anti-inflammatory strategies in this context.…”

The immune system and cardiac repair

“…C-reactive Protein (CRP) and Serum Amyloid P (SAP) Component are the prototypes of the short pentraxin family and are mainly produced by the liver as acute phase proteins in response to inflammatory signals [20]. It has been suggested that CRP deposition in the infarct may locally activate the complement cascade accentuating cardiomyocyte injury [21], [22]. On the other hand the prototypical long pentraxin PTX3 is a multifunctional protein at the crossroads between immunity and inflammation.…”