Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age

Abstract

Cytokines and inflammation have been implicated in the pathogenesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor ␣ in response to lipopolysaccharide than those with WT STAT3. Furthermore, histologic examination of the cardiomyocyte-restricted STAT3-deficient mice reveals a dramatic increase in cardiac fibrosis in aged mice. Although no overt signs of heart failure are present in young STAT3-deficient mice, they spontaneously develop heart dysfunction with advancing age. These results indicate the crucial functions of STAT3 in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure.

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

“…Mitochondrial dysfunction and mitochondria oxidative stress have linked to age-related heart diseases. [36][37][38][39] To examine the effects of age on heart function of Gab1-cKO mice, we continued to monitor cardiac function of Gab1-WT and Gab1-cKO mice via echocardiography as they aged from 4 weeks to 6 months. We found that at 3 months of age, Gab1-cKO mice exhibited a decreased EF and increased LVIDd, without obvious morphological changes and no apparent differences in LVPW compared with Gab1-WT mice.…”

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

“…Recently, STAT3 has been shown to be necessary to control systemic inflammation (Jacoby et al, 2003;Sander et al, 2010). A previous study has also shown that Bcl2 overexpression protects P<0.01 (LPS vs LPS+Aza+TSA, and LPS+Aza+TSAvs LPS+Aza+TSA+ SB202190).…”

Pathophysiology of heart failure and frailty: a common inflammatory origin?

“…DNA damage, impaired autophagy, and mitochondrial dysfunction are biological processes that occur in both aging and HF, and these processes can lead to metabolic dysfunction, cellular senescence, and ultimately cellular necrosis, leading to activation of innate immunity and the production of inflammatory mediators into the circulation. The protein STAT3 limits redox stress and promotes mitochondrial function, and mice lacking STAT3 have increased proinflammatory cytokines and cardiac fibrosis with age (Jacoby et al ., 2003). Additionally, senescence‐prone mice have elevated levels of pro‐inflammatory cytokines including IL‐1β, a signature cytokine of inflammasome activation (Saito & Papaconstantinou, 2001; Karuppagounder et al ., 2016).…”