Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets

Abstract

The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiologyrelated pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not described in any previous study of cardiac disorders was observed. Two significantly altered gene networks of particular interest and possible interdependence centered around the cysteine-rich angiogenic inducer 61 (CYR61) and adiponectin (APN) gene. CYR61 overexpression, as in human DCMi hearts in situ, was similarly induced by inflammatory cytokines in vascular endothelial cells in vitro. APN was strongly downregulated in DCMi hearts and completely abolished cytokine-dependent CYR61 induction in vitro. Dysbalance between the CYR61 and APN networks may play a pathogenic role in DCMi and contain novel therapeutic targets. Multiple immune cellassociated genes were also deregulated (e.g., chemokine ligand 14, interleukin-17D, nuclear factors of activated T

Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

“…However, previous studies have also implicated Cyr61 in the pathogenesis of inflammatory diseases, such as atherosclerosis (9), inflammatory cardiomyopathy (10), and Graves' ophthalmopathy (11). In a rat model of bacteria-induced apical periodontitis, we found that osteoblastic expression of Cyr61 correlates with the severity of inflammation-associated bone loss (12).…”

Postoperative Accumulation of Cyr61/CCN1 in Surgical Wound Fluid Precedes Cytokine Activation and is Disparate from Systemic Alterations

“…Studies have connected deregulations of CCN1 to a variety of diseases associated with chronic inflammation, such as rheumatoid arthritis [27], atherosclerosis [28], infectious myocarditis [29], inflammatory bowel disease [30], chronic obstructive pulmonary disorder [31] and several cancers [7]. However, experimental studies have also suggested a role for CCN1 in acute inflammation by demonstrating its ability to promote cytokine secretion [21,32] and support the adhesion of platelets [33], and monocytes/macrophages [21,34].…”

Myocardial Extracellular Matrix

“…271 The overexpression of CCN-1 in experimental autoimmune myocarditis confirms the potential role of CCN-1 on leukocyte behavior by decreasing cardiac inflammation. 272,273 Finally, although the in vivo effects of CCN-4 upregulation after MI remain unclear, in vitro studies suggest a role for CCN-4 in fibroblast proliferation and transduction of prohypertrophic and prosurvival signals in cardiomyocytes.…”