Cardiac-specific ablation of theSTAT3gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling

Abstract

Enomoto D, Obana M, Miyawaki A, Maeda M, Nakayama H, Fujio Y. Cardiac-specific ablation of the STAT3 gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling. Am J Physiol Heart Circ Physiol 309: H471-H480, 2015. First published June 8, 2015 doi:10.1152/ajpheart.00730.2014.-STAT3 is a cardioprotective molecule against acute myocardial injury; however, recent studies have suggested that chronic STAT3 activation in genetically modified mice was detrimental after myocardial infarction (MI). In the present study, we assessed the biological significance of STAT3 activity in subacute MI using tamoxifen (TM)-inducible cardiac-specific STAT3 knockout (STAT3 iCKO) mice. After coronary ligation, STAT3 was rapidly activated in hearts, and its activation was sustained to the subacute phase. To make clear the pathophysiological roles of STAT3 activation specifically in subacute MI, MI was generated in STAT3 iCKO mice followed by TM treatment for 14 consecutive days beginning from day 11 after MI, which ablated the STAT3 gene in the subacute phase. Intriguingly, mortality was increased by TM treatment in STAT3 iCKO mice, accompanied by an increased heart weight-to-body weight ratio. Masson's trichrome staining demonstrated that cardiac fibrosis was dramatically exacerbated in STAT3 iCKO mice 24 days after MI (fibrotic circumference: 58.3 Ϯ 6.7% in iCKO mice and 40.8 Ϯ 9.3% in control mice), concomitant with increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. Echocardiography clarified that cardiac function was deteriorated in STAT3 iCKO mice (fractional shortening: 20.6 Ϯ 4.1% in iCKO mice and 29.1 Ϯ 6.0% in control mice). Dihydroethidium fluorescence analysis revealed that superoxide production was increased in STAT3 iCKO mice. Moreover, immunohistochemical analyses revealed that capillary density was decreased in STAT3 iCKO mice. Finally, STAT3 deletion in subacute MI evoked severe cardiac hypertrophy in the border zone. In conclusion, the intrinsic activity of STAT3 in the myocardium confers the resistance to cardiac remodeling in subacute MI. signal transduction; cardiac remodeling; signal transducer and activator of transcription 3 NEW & NOTEWORTHYWe examined, for the first time, the cardioprotective role of STAT3 in the subacute phase after myocardial infarction in a time-specific manner. The basal activity of STAT3 in the postinfarct myocardium confers the resistance to cardiac remodeling in subacute myocardial infarction, preventing the progression of heart failure.

Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis

“…Indeed, there was a remarkable difference in frequency between pSTAT3 positive cells and proliferative marker positive cells in EAM myocardium, indicating that additional signals are involved in the regulation of adult cardiomyocyte proliferation. In this context, it is interesting that STAT3 is also activated in infarcted hearts and mediates cardioprotection 8, 18 , but cardiomyocyte proliferation remains at a substantially lower rate in MI than that in EAM 26–28, 55 . The difference between these two models might be explained by different expression levels of positive and/or negative regulators of cell proliferation.…”

“…Immunoblotting was performed as described previously 18 . Antibodies were used at 1/500 and are listed in Supplementary Table S2.…”

“…Recently, it has also been documented that STAT3 is required for regeneration of neonatal mouse hearts by using ventricular amputation model 12 , while ventricular dissection results in cardiac scar formation without repair in adult mouse hearts 15 . It should also be noted that STAT3 is activated in post-infarct myocardium but that STAT3 activation fails to induce cardiomyocyte proliferation at significant frequency in adult mouse hearts 8, 15, 17, 18 , though myocardial activation of STAT3 contributes to cardioprotection 7–9 and angiogenesis 19, 20 , leading to prevention of adverse cardiac remodeling.…”

Exogenous IL‐19 attenuates acute ischaemic injury and improves survival in male mice with myocardial infarction

“…The transcription factor STAT3 is a key regulator of cell‐to‐cell communication in the heart (Haghikia et al ., ), and is not only cardioprotective against acute myocardial injury (Obana et al ., , ) but also confers resistance to cardiac remodelling in subacute MI, preventing the progression of heart failure (Enomoto et al ., ). In our experiments, IL‐19 treatment increased the DNA‐binding activity of STAT3 in myocardium of mice with MI.…”

Stat proteins as intracellular regulators of resistance to myocardial injury in the context of cardiac remodeling and targeting for therapy

“…Finally, cardiac fibrosis was favored by increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. 31 Atrial fibrillation (AF) is such an important factor of cardiovascular disease-related morbidity and mortality that Zheng et al investigated the role of AT1, Ang II and cell death, and are transmitted after coupling this receptor with an activator of caspases -the FADD protein that is also stimulated by TNF-α. 20 The antiapoptotic effects were attributed to the LIF-induced expression of Bcl-xL with very questionable signal mediation by STAT1 through gp130.…”