Signal transducer and transcriptional activation 1 protects against pressure overload‐induced cardiac hypertrophy

Abstract

Signal transducers and transcriptional activation 1 (Stat1) is a member of the STATs family, and its role in various biological responses, including cell proliferation, differentiation, migration, apoptosis, and immune regulation has been extensively studied. We aimed to investigate its role in pathological cardiac hypertrophy, which is currently poorly understood. Experiments using H9C2 cardiomyocytes, Stat1, and IfngR cardiomyocyte‐specific knockout mice revealed that Stat1 had a protective effect on cardiac hypertrophy. Using transverse aortic constriction (TAC)‐induced cardiac hypertrophy in mice, we analyzed the degree of hypertrophy using echocardiography, pathology, and at the molecular level. Mice lacking Stat1 had more pronounced cardiac hypertrophy and fibrosis than wild‐type TAC mice. Analysis of the molecular mechanisms suggested that Stat1 downregulated the mRNA levels of hypertrophy and fibrosis markers to inhibit cardiac hypertrophy, and promotes mitochondrial fission through the Ucp2/P‐Drp1 pathway, enhancing mitochondrial function, and increasing compensatory myocardial ATP production in the compensatory phase for cardiac hypertrophy inhibition. Overall, this comprehensive analysis revealed that Stat1 inhibits cardiac hypertrophy by downregulating hypertrophic and fibrotic marker genes and enhancing the mitochondrial function to enhance cardiomyocyte function through the Ucp2/P‐Drp1 signaling pathway.

Transcriptomic and Lipidomic Mapping of Macrophages in the Hub of Chronic Beta-Adrenergic-Stimulation Unravels Hypertrophy-, Proliferation-, and Lipid Metabolism-Related Genes as Novel Potential Markers of Early Hypertrophy or Heart Failure

“…In addition, ECH macrophages were characterized by an increased expression of Pdk1 (pyruvate deshydrogenase) coding for a rate limiting enzyme of glucose oxidation [ 79 ]. ECH macrophages also exhibited an induction of Ucp2 (mitochondrial uncoupling protein 2), that plays a cardioprotective role in cardiac hypertrophy promoting mitochondrial fission, ATP synthesis and a decreased ROS production [ 80 ] ( Figure 5 ).…”

Pro‐atherogenic actions of signal transducer and activator of transcription 1 serine 727 phosphorylation in LDL receptor deficient mice via modulation of plaque inflammation

“…Both IFN-γ and STAT1 have been found to protect against pressure overload-induced cardiac hypertrophy. 45,46 Future studies should therefore investigate the effect of STAT1 S727A modification on cardiac hypertrophy induced by sustained pressure overload. In addition, as STAT1 has been previously shown to cause loss of cardiac myocytes by promoting apoptosis and also reducing cardioprotective autophagy, 47 the role of STAT1 S727 phosphorylation in these and other processes that contribute to cardiac hypertrophy needs to be investigated.…”

“…The molecular mechanisms underlying decreased cardiac hypertrophy in LDLR −/− /STAT1 S727A mice and why these were not seen in ERK1 deficient mice remains to be determined and should be investigated in future studies. Both IFN‐γ and STAT1 have been found to protect against pressure overload‐induced cardiac hypertrophy 45,46 . Future studies should therefore investigate the effect of STAT1 S727A modification on cardiac hypertrophy induced by sustained pressure overload.…”

The lncRNA Sros1 is involved in the development of cardiac fibrosis by regulating the TGF-β/SMAD2/3 signaling cascade

“…Interestingly, although in infectious myocarditis or autoimmune myocarditis, IFN-γ has an important therapeutic effect [6], long-term use of IFN-γ can cause cardiomyocyte necrosis and myocardial fibrosis, eventually inducing HF [4,9]. Besides, researchers also prompted that STAT1/3 had the ability in regulating cardiac fibrosis [13][14][15]. However, whether Sros1 play a role in the development of cardiac fibrosis and HF is still unknown.…”