Inhibition of signal transducer and activator of transcription 3 (STAT3) attenuates interleukin-6 (IL-6)-induced collagen synthesis and resultant hypertrophy in rat heart.

Abstract

IL-6 has been shown to play a major role in collagen up-regulation process during cardiac hypertrophy, although the precise mechanism is still not known. In this study we have analyzed the mechanism by which IL-6 modulates cardiac hypertrophy. For the in vitro model, IL-6-treated cultured cardiac fibroblasts were used, whereas the in vivo cardiac hypertrophy model was generated by renal artery ligation in adult male Wistar rats (Rattus norvegicus). During induction of hypertrophy, increased phosphorylation of STAT1, STAT3, MAPK, and ERK proteins was observed both in vitro and in vivo. Treatment of fibroblasts with specific inhibitors for STAT1 (fludarabine, 50 μM), STAT3 (S31-201, 10 μM), p38 MAPK (SB203580, 10 μM), and ERK1/2 (U0126, 10 μM) resulted in down-regulation of IL-6-induced phosphorylation of specific proteins; however, only S31-201 and SB203580 inhibited collagen biosynthesis. In ligated rats in vivo, only STAT3 inhibitors resulted in significant decrease in collagen synthesis and hypertrophy markers such as atrial natriuretic factor and β-myosin heavy chain. In addition, decreased heart weight to body weight ratio and improved cardiac function as measured by echocardiography was evident in animals treated with STAT3 inhibitor or siRNA. Compared with IL-6 neutralization, more pronounced down-regulation of collagen synthesis and regression of hypertrophy was observed with STAT3 inhibition, suggesting that STAT3 is the major downstream signaling molecule and a potential therapeutic target for cardiac hypertrophy.

• Authors: Saiful Anam Mir, Arunachal Chatterjee, Arkadeep Mitra, Kanchan Pathak, Sushil K Mahata, Sagartirtha Sarkar
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 4 Pg. 2666-77 (Jan 20 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22157761 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Butadienes
• Enzyme Inhibitors
• Imidazoles
• Interleukin-6
• Nitriles
• Pyridines
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Stat1 protein, rat
• Stat3 protein, rat
• U 0126
• Collagen
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Vidarabine
• SB 203580
• fludarabine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Butadienes (pharmacology)
• Cardiomegaly (chemically induced, genetics, metabolism, pathology)
• Cells, Cultured
• Collagen (biosynthesis, genetics)
• Disease Models, Animal
• Down-Regulation (drug effects, genetics)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, genetics, metabolism)
• Fibroblasts (metabolism, pathology)
• Humans
• Imidazoles (pharmacology)
• Interleukin-6 (adverse effects, genetics, metabolism, pharmacology)
• MAP Kinase Signaling System (drug effects, genetics)
• Male
• Nitriles (pharmacology)
• Phosphorylation (drug effects, genetics)
• Pyridines (pharmacology)
• Rats
• Rats, Wistar
• STAT1 Transcription Factor (genetics, metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Vidarabine (analogs & derivatives, pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)