Myocardial osteopontin expression is associated with collagen fibrillogenesis in human dilated cardiomyopathy

Abstract

Background: Osteopontin (OPN), an extracellular matrix (ECM) protein, plays an important role in myocardial remodeling by promoting collagen synthesis and accumulation in experimental animal models. Aims: We hypothesized that OPN could be expressed in myocardial tissues and contribute to collagen accumulation and myocardial dysfunction in human dilated cardiomyopathy (DCM). Methods and results: Endomyocardial biopsy tissues were obtained from 51 patients with DCM and 15 controls by right ventricular endomyocardial biopsy. OPN, collagen types I (Col I) and III (Col III) mRNA levels were measured by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The cellular source of OPN was analyzed using immunohistochemistry and in situ hybridization. Myocardial collagen volume fraction (CVF) was determined by digital planimetry. OPN, Col I and Col III mRNA levels were higher in DCM patients than in controls ( Pb0.01). OPN mRNA levels were positively correlated with Col I levels and CVF in DCM patients (OPN vs. Col I: r=0.60, Pb0.01; OPN vs. CVF: r=0.52, Pb0.001). Immunostaining of OPN was present in cardiomyocytes from DCM patients. In situ hybridization identified cardiomyocytes as the major source of OPN mRNA transcription in DCM patients. OPN and Col I mRNA levels were highly expressed in the DCM subgroup with large left ventricular (LV) end-systolic diameter (LVESDz54.5 mm) or low LV ejection fraction (LVEFb29.5%). There was a weak positive correlation between OPN mRNA levels and LV end-systolic diameter (r=0.39, Pb0.01). Levels of OPN mRNA were also negatively correlated with LV ejection fraction (r=À0.43, Pb0.01). Conclusions: These results suggest that OPN may play a pivotal role in the development of Col-I-induced cardiac fibrosis and dysfunction in human DCM.

IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice

“…More specifically, as reviewed by Okamoto (24), OPN connects fibroblasts, cardiomyocytes, and the extracellular matrix through focal and fibrillar adhesions and initiates cell signaling cascades (26). OPN expression is substantially upregulated during remodeling in wound healing and myocardial injury (31). Importantly, as a mediator of tissue remodeling, OPN has many diverse cellular roles including regulation of cardiac fibroblast survival and differentiation (18), formation of a matrix to adhere or attract myocardial constituent fibroblasts and endothelial cells to the injury site, and promotion of scar formation as reviewed by Denhardt et al (10).…”

Differential coupling of Arg- and Gly389 polymorphic forms of the β1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs

“…Opn binds some integrins, certain variants of CD44, and ECM components (23). In humans, Opn expression has been associated with dilated cardiomyopathy (22,27), hypertrophic cardiomyopathy, and ventricular tachycardia (15). Of note, Opn is necessary for increased atrial natriuretic factor (ANF) production in mice at an early stage of cardiac hypertrophy from chronic pressure overload (33).…”

Osteopontin

“…21 35 S-Labeled antisense and sense RNA probes for detection of murine OPN mRNA were synthesized by in vitro transcription from the dual-promoter plasmid TOPO-mOPN containing an 879-bp OPN cDNA fragment. CVB3 positive-strand RNA was detected in tissues using single-stranded 35 S-labeled RNA probes, which were synthesized from the dual-promoter plasmid pCVB3-R1. Control RNA probes were obtained from the vector pSPT18.…”

“…35 S-Labeled antisense and sense hOPN RNA probes were synthesized by in vitro transcription from the dual-promoter plasmid pGEM-hOPN containing a 350-bp cDNA fragment. Pretreatment, hybridization, and washing conditions of dewaxed 5-m paraffin tissue sections were performed as described previously.…”