Abstract
Regenerating islet‐derived 3γ (Reg3γ) is a multifunctional protein, associated with various tissue injuries and inflammatory states. Since chronic inflammation is characteristics also for heart failure, the aim of this study was to characterize Reg3γ expression in cardiac inflammatory conditions. Reg3γ expression was studied in experimental rat models of myocardial infarction (MI) and pressure overload in vivo. For cell culture studies neonatal rat cardiac myocytes (NRCMs) were used. In addition, adenovirus‐mediated gene transfer of upstream mitogen‐activated protein kinase (MAPK) kinase 3b and p38α MAPK in vivo and in vitro was performed. Reg3γ mRNA (12.8‐fold, P < 0.01) and protein (5.8‐fold, P < 0.001) levels were upregulated during the postinfarction remodeling at day 1 after MI, and angiotensin II (Ang II) markedly increased Reg3γ mRNA levels from 6 h to 2 weeks. Immunohistochemistry revealed that the Ang II‐induced expression of Reg3γ was localized into the cardiac fibroblasts and myofibroblasts of the proliferating connective tissue in the heart. Stretching and treatments with endothelin‐1, lipopolysaccharide (LPS), and fibroblast growth factor‐1 increased Reg3γ mRNA levels in NRCMs. SB203580, a selective p38 MAPK inhibitor, markedly attenuated LPS and mechanical stretch‐induced upregulation of Reg3γ gene expression. Moreover, combined overexpression of MKK3bE and WT p38α increased Reg3γ gene expression in cultured cardiomyocytes in vitro and in the rat heart in vivo. Our study shows that cardiac stress activates Reg3γ expression and p38 MAPK is an upstream regulator of Reg3γ gene expression in heart. Altogether our data suggest Reg3γ is associated with cardiac inflammatory signaling.
Highlights
Heart failure (HF) is a complex clinical syndrome, and one of the leading causes of morbidity and mortality worldwide (Braunwald 2013)
This study showed that activation of the Janus family tyrosine kinases (JAK) 1-signal transducers and activators of transcription (STAT) 3 pathway was required for Reg3b expression in cardiomyocytes
Comparable to the results obtained by the DNA microarray analysis of hypertrophied hearts of spontaneously hypertensive rats (SHR) (Rys€a et al 2005), left ventricular Regenerating islet-derived 3c (Reg3c) mRNA levels were 4.4-fold higher in 20-month-old SHR (P < 0.001) compared with age-matched normotensive Wistar Kyoto rats (WKY) rats (Fig. 1A)
Summary
Heart failure (HF) is a complex clinical syndrome, and one of the leading causes of morbidity and mortality worldwide (Braunwald 2013). Chronic HF is associated with a combination of neurohormonal disturbance, imbalance between the expression of extracellular matrix proteins, increased oxidative stress and myocyte injury (Braunwald 2013). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
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