Interferon regulatory factors in heart: stress response beyond inflammation.

C ardiac hypertrophy and pathological remodeling are hallmarks of cardiomyopathy associated with many pathological stressors, such as mechanic overload, oxidative injury, hormonal stimulation, or viral infection. Transcriptional regulation is key to this process, involving well-established transcription factors, such as NFAT, GATA, MEF2, and NF-κB among others. 1 They function as the downstream effectors for upstream signaling to alter the cardiac transcriptome that ultimately leads to pathological changes in cardiomyocyte morphology and function. Therefore, uncovering the molecular basis of the regulatory circuit for cardiac gene expression has been a major focus of intense research efforts. In this issue, a study from the laboratory of Dr Hongliang Li expands the complexity of the transcriptional network in the heart by uncovering yet another new player from an unexpected family. 2 Interferon regulatory factors (IRFs) are a group of transcription factors that were first identified for their inducible expression in response to interferon signaling. 3 Members of the IRF family play critical roles in antiviral responses, inflammatory regulation, cytokine signaling, cell death, growth, and differentiation. 3 Interferon exerts potent antipa-thogen responses in the host immune system and have been used as therapeutic agents against viral infections, such as hepatitis C. 4 The link between interferon function and heart disease was first observed in interferon-based antiviral therapies where interferon-α treatment was reported to cause transient or irreversible cardiomyopathies. 5–7 In contrast, conflicting effects of interferon γ were observed in both clinical and animal studies, whereas interferon γ treatment was beneficial for viral-induced myocarditis 8 ; it was also reported to cause cardiomyopathy and dysfunction in transgenic mice. 9 Genetic knockout of interferon γ receptor reduced angiotensin II–induced hypertrophy and remodeling. In contrast, genetic ablation of interferon γ enhanced pathological hypertrophy and diastolic heart failure. These functional effects of inter-feron on cardiac hypertrophy and pathological remodeling raise important questions about the role of downstream IRFs in cardiac pathology. Do they affect cardiomyocytes indirectly via infiltrating inflammatory cells or do they function directly to regulate cardiac hypertrophy and remodeling in cardio-myocyte in a cell-autonomous fashion? More importantly, are IRFs involved specifically in interferon-triggered cardiomy-opathy or broadly in other pathological stress responses in the heart? A series of recent reports from the laboratory of Dr. Hongliang Li began to address these questions on the basis of sophisticated genetic analysis both in cultured myocytes and in intact mouse hearts. In the study published in the current issue of Hypertension, …