Peroxisome Proliferator–Activated Receptor-γ Activation Prevents Sepsis-Related Cardiac Dysfunction and Mortality In Mice

Abstract

Background Cardiac dysfunction with sepsis is associated with both inflammation and reduced fatty acid oxidation (FAO). We hypothesized that energy deprivation accounts for sepsis-related cardiac dysfunction. Methods and Results E. coli lipopolysaccharide (LPS) administered to C57BL/6 mice (WT) induced cardiac dysfunction and reduced FAO and mRNA levels of peroxisome proliferator-activated receptor (PPAR) α and its downstream targets within 6-8h. Transgenic mice in which cardiomyocyte-specific expression of PPARγ is driven by the alpha myosin heavy chain promoter (αMHC-PPARγ) were protected from LPS-induced cardiac dysfunction. Despite a reduction in PPARα, FAO and associated genes were not decreased in hearts of LPS-treated αMHC-PPARγ mice. LPS treatment, however, continued to induce inflammation-related genes, such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α in hearts of αMHC-PPARγ mice. Treatment of WT mice with LPS and the PPARγ agonist rosiglitazone, but not the PPARα agonist (WY-14643), increased FAO, prevented LPS-mediated reduction of mitochondria and treated cardiac dysfunction, as well as it improved survival despite continued increases in the expression of cardiac inflammatory markers. Conclusion Activation of PPARγ in LPS-treated mice prevented cardiac dysfunction and mortality despite development of cardiac inflammation and PPARα downregulation.

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

“…Furthermore, the NOX2 inhibitor apocynin prevents systolic dysfunction in vivo, but it does not cause a reduction in circulating proinflammatory cytokines or cardiac tissue inflammatory gene expression, demonstrating that cardiac contractility and systemic inflammation can be dissociated. This finding is consistent with our previous findings showing that induction of cardiac fatty acid oxidation and energy production improved cardiac function prior to alleviation of inflammation (11,13). These new findings, in combination with our prior work, suggest a crucial role for restoration of mitochondrial function and cardiac energetics as a way to maintain cardiac function in sepsis, independently of systemic inflammation, at least for the early stage of the disease.…”

“…Samples were normalized against 18S ribosomal RNA. The sequences of the primers have been described previously (11).…”

“…To assess the significance of NOX2 activation in septic cardiac dysfunction in vivo, we used a mouse model of LPS-induced endotoxemia (11,28). Wildtype (WT) mice were injected with LPS, which is known to decrease cardiac contractility, and then we assessed cardiac function by echocardiography.…”

“…A variety of mechanisms have been proposed to explain cardiomyopathy during sepsis, including increased reactive oxygen species (ROS) as an important part of the pathophysiology (9,10). Mitochondrial dysfunction has been a consistent finding in sepsis models, with decreased mitochondrial oxidative phosphorylation and decreased transcription of mitochondrial genes (11)(12)(13). Abnormalities of intracellular calcium handling have also been observed in cardiomyocytes from animal models of sepsis (14)(15)(16)(17).…”

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

“…PPARγ prevents severe RVF secondary to pulmonary arterial hypertension: Accumulating evidence has suggested that PPARγ agonist could protect the heart from adverse remodeling after ischemia injury, [16][17][18] which is mainly associated with left ventricular function. In order to distinguish the PPARγ protective effect on RV from LV and gain more insight into the protective effects related to PPARγ, echocardiographic and Doppler flow measurements were carried out for both RV and LV.…”