ArticleCardiovascular research2025
Cardiac ischaemia/reperfusion in pigs and mice increases cardiomyocyte Krüppel-like factor 5 that aggravates tissue injury and remodelling.
Article in Cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Targeting the undruggable transcription factor, KLF5, with a peptidomimetic small molecule, NC114, attenuates pressure overload-induced cardiac remodeling and fibrosis.Scientific reports · 2026Article
- Gene expression profiling of KLF4 and KLF5 in visceral adipose tissue of obese women: insights into adipogenic and metabolic regulation.Lipids in health and disease · 2025Article
- Empagliflozin restores cardiac metabolism and suppresses immune activation in acute myocardial infarction.Atherosclerosis · 2025Article
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Abstract
aimsActivation of the transcriptional factor Krüppel-like factor 5 (KLF5) is detrimental to chronic heart failure. We explored the involvement of KLF5 in myocardial ischaemia/reperfusion injury. METHODS AND
resultsYorkshire pigs underwent 75' of ischaemia, followed by 3 or 24 h of reperfusion. C57BL/6J mice underwent 30' of ischaemia, followed by 10', 2, 12, 24 h, or 4 weeks of reperfusion. Hearts and isolated cardiomyocytes (CMs) were analysed for gene expression. We assessed cardiac function, infarct size (IS), oxidative stress, and fibrosis in mice subjected to pharmacologic or genetic KLF5 inhibition, as well as pharmacologic inhibition of NADPH oxidases or glucose transporter (GLUT)1 and GLUT4. Bulk RNA sequencing, untargeted 1H-NMR metabolomics, and LC-MS lipidomics were performed. Isolated primary murine CMs were infected with recombinant adenovirus expressing KLF5. During reperfusion, CM KLF5 expression was increased in porcine and murine hearts. Pharmacologic or CM-specific genetic inhibition of KLF5 reduced IS and improved cardiac function in mice. Importantly, acute KLF5 inhibition during early reperfusion suppressed fibrosis and preserved systolic cardiac function 4 weeks post-ischaemia/reperfusion. This improvement was associated with lower NADPH-oxidase 4 (NOX4) expression, less oxidative stress, and suppressed inflammation and cell apoptosis. Pharmacologic inhibition of NOX4 conferred the same benefit. Metabolomic analysis indicated that KLF5 inhibition lowered glucose-derived metabolites (UDP-glucose and lactate) at early reperfusion. Accordingly, cardiac GLUT1 and GLUT4 levels were increased with ischaemia/reperfusion, which was reverted by KLF5 inhibition. Pharmacologic inhibition of both GLUT1 and GLUT4 reduced IS. Finally, myocardial KLF5 overexpression increased GLUT1 mRNA levels and mouse mortality.
conclusionIschaemia/reperfusion increases CM KLF5 expression in pigs and mice. This constitutes a central element of myocardial injury pathophysiology and is associated with stimulation of GLUT1 and GLUT4 expression, activation of NOX4, oxidative stress, inflammation, and apoptosis. Acute KLF5 inhibition during reperfusion constitutes a novel therapeutic approach against myocardial ischaemia/reperfusion injury.
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