Related Experiment Video
Updated: May 31, 2025
Standardized Colon Ascendens Stent Peritonitis in Rats - a Simple, Feasible Animal Model to Induce Septic Acute Kidney Injury
Published on: February 15, 2022
KW-2449 Ameliorates Cardiac Dysfunction in a Rat Model of Sepsis-Induced Cardiomyopathy
Jie Chen1, Wei-Jian Zhang1, Xiao-Yu Liu1
1Department of Emergency, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100029, China.
Abstract:
KW-2449 is a novel multitargeted kinase inhibitor that has been reported to alleviate chronic inflammation and altered immunity during the treatment of autoimmune diseases. The aim of the study was to investigate the effect of KW-2449 on sepsis-induced cardiomyopathy (SIC). A rat model of moderate SIC was induced using the cecal ligation and puncture (CLP) method. KW-2449 was administered to rats at 10 mg/kg for 3 consecutive days by intraperitoneal injection. At 24 hours after CLP, echocardiography, electrocardiogram, and hemodynamic analyses were performed. Blood and cardiac tissues were collected for further analysis. RNA sequencing (RNA-seq) analyses were used to identify the key genes affected by KW-2449 treatment during SIC. KW-2449 improved the liver dysfunction in septic rats. KW-2449 significantly improved left ventricular (LV) systolic function and hemodynamics compared to the CLP group. KW-2449 suppressed the systemic inflammatory response, decreased myocardial inflammation and cell apoptosis in the CLP rats. RNA-seq analyses indicated that there were a total of 2256 differentially expressed genes in the CLP group compared to the Control group, among which 63 genes were down-regulated and 59 genes were up-regulated by KW-2449. Specifically, Pparα was identified as a key target gene of KW-2449 in the treatment of SIC by RNA-seq analysis.KW-2449 also significantly upregulated the protein expression of Pparα in the LV tissue of septic rats. KW-2449 reduced systemic inflammation, cardiac inflammation, and improved cardiac dysfunction in the CLP-induced SIC rat model. The underlying mechanism of the cardio-protective role of KW-2449 in the CLP-induced SIC might be related to Pparα.
Insights
KW-2449, a kinase inhibitor, improved cardiac function and reduced inflammation in a rat model of sepsis-induced cardiomyopathy (SIC). Its protective effects may involve the key target gene Pparα.
Area of Science:
- Pharmacology
- Cardiology
- Immunology
Background:
- Sepsis-induced cardiomyopathy (SIC) is a severe complication of sepsis, characterized by cardiac dysfunction.
- Kinase inhibitors have shown potential in modulating inflammatory and immune responses.
- KW-2449 is a novel multitargeted kinase inhibitor with reported anti-inflammatory properties.
Purpose of the Study:
- To investigate the therapeutic effects of KW-2449 on sepsis-induced cardiomyopathy (SIC) in a rat model.
- To elucidate the underlying molecular mechanisms, including gene expression changes, associated with KW-2449 treatment in SIC.
Main Methods:
- A rat model of moderate SIC was established using the cecal ligation and puncture (CLP) method.
- KW-2449 was administered intraperitoneally at 10 mg/kg for 3 consecutive days.
- Cardiac function was assessed using echocardiography, electrocardiogram, and hemodynamic analyses. RNA sequencing (RNA-seq) was employed to identify differentially expressed genes.
Main Results:
- KW-2449 treatment significantly improved left ventricular systolic function and hemodynamics in septic rats.
- KW-2449 suppressed systemic inflammation, myocardial inflammation, and reduced cardiac cell apoptosis.
- RNA-seq identified Pparα as a key target gene, with KW-2449 upregulating its protein expression in cardiac tissue.
Conclusions:
- KW-2449 demonstrates significant cardio-protective effects in a rat model of SIC.
- The therapeutic mechanism of KW-2449 in SIC may be mediated through the upregulation of Pparα.
- KW-2449 holds promise as a potential therapeutic agent for sepsis-induced cardiomyopathy.
