Key result
Cardiomyocyte-specific PAI-1 knockout mice displayed significantly worse cardiac fibrosis and differential expression of 978 genes compared to controls after left ventricular pressure overload.
Why the study?
Global PAI-1 knockout mice develop cardiac fibrosis, but whether cardiomyocyte PAI-1 specifically confers cardioprotective effects during left ventricular pressure overload was unknown.
Does cardiomyocyte-specific PAI-1 knockout influence cardiac fibrosis and the cardiac transcriptome in response to left ventricular pressure overload in mice?
Does cardiomyocyte-specific PAI-1 knockout influence cardiac fibrosis and the cardiac transcriptome in response to left ventricular pressure overload in mice?
Cardiomyocyte PAI-1 plays a crucial cardioprotective role by limiting cardiac fibrosis and regulating the stress-response transcriptome network during left ventricular pressure overload.
Answers are grounded in this paper and cite their sources.
Suggests cardiomyocyte PAI-1 protects against fibrosis in pressure overload; hypothesis-generating for human therapeutic targeting.
Plasminogen activator inhibitor-1 (PAI-1) is a specific and rapid-acting inhibitor of endogenous plasminogen activators (uPA and tPA). The global PAI-1 knockout mice (PAI-1KO) develop age-dependent cardiac-selective fibrosis, and young global PAI-1KO mice exhibit augmented susceptibility to developing cardiac fibrosis in response to hypertension. Here, we tested the hypothesis that cardiomyocyte PAI-1 is necessary to provide cardioprotective effects in a left ventricular pressure overload-induced murine model of cardiac hypertrophy and fibrosis using cardiomyocyte-specific PAI-1 knockout (cmPAI-1KO) mice. The results revealed that cmPAI-1KO mice display significantly worse cardiac fibrosis than controls. To investigate the molecular mechanisms responsible for these effects, genome-wide cardiac transcriptome analysis was performed. Loss of cardiomyocyte PAI-1 led to differential expression of 978 genes compared to controls in response to left ventricular pressure overload. Pathway enrichment analysis identified the inflammatory response, cell substrate adhesion, regulation of cytokine production, leukocyte migration, extracellular matrix organization, and cytokine-mediated signaling pathways as being significantly upregulated in cmPAI-1KO hearts. Conversely, specific epigenetic repressors, cation transmembrane transport, muscle system processes, and nitric oxide signaling were significantly downregulated in cmPAI-1KO hearts compared to control hearts in response to left ventricular pressure overload. Collectively, the present study provides strong evidence of the impact of cardiomyocyte PAI-1 in regulation of the transcriptome network involved in the cardiac stress response. In response to stress, the deregulatory impact of cardiomyocyte PAI-1 loss on the cardiac transcriptome may be the underlying cause of cardiac-selective accelerated fibrogenesis in global PAI-1-deficient mice.
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Ghosh et al. (2022) studied Left ventricular pressure overload-induced cardiac hypertrophy and fibrosis. Cardiomyocyte-specific PAI-1 knockout (cmPAI-1KO) vs. Controls was evaluated on Cardiac fibrosis and cardiac transcriptome changes. Cardiomyocyte-specific PAI-1 knockout mice displayed significantly worse cardiac fibrosis and differential expression of 978 genes compared to controls after left ventricular pressure overload.
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