CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity
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Published on: April 18, 2025
Li Cao1, Xing Qin2, Matthew R Peterson3
1School of Pharmacy, University of Wyoming, College of Health Sciences, Laramie, WY 82071, USA; College of Pharmaceutical Sciences, Soochow University, Soochow, Jiangsu 215123, PR China.
Insights
Mice lacking CARD9 (caspase recruitment domain-containing protein 9) showed improved heart function and metabolic health when fed a high-fat diet. This suggests CARD9 plays a key role in obesity-induced inflammation and cardiovascular problems.
Area of Science:
- Cardiovascular Biology
- Immunology
- Metabolic Syndrome
Background:
- Obesity is linked to chronic inflammation and cardiovascular dysfunction.
- Caspase recruitment domain-containing protein 9 (CARD9) regulates innate immune responses in macrophages, influencing pro-inflammatory cytokine production.
Purpose of the Study:
- To investigate the role of CARD9 in mediating obesity-induced pro-inflammatory signaling and subsequent myocardial dysfunction.
- To determine if CARD9 knockout protects against high-fat diet-induced cardiac and metabolic impairments.
Main Methods:
- C57BL/6 wild-type and CARD9 knockout mice were fed normal or high-fat diets for 5 months.
- Cardiac function was assessed via echocardiography, and cardiomyocyte contractility was measured.
- Macrophage infiltration, pro-inflammatory cytokines (IL-6, IL-1β, TNFα), MAPK phosphorylation, and autophagy markers (LC3B, p62) were analyzed.
Main Results:
- CARD9 knockout alleviated high-fat diet-induced insulin resistance and glucose intolerance.
- Myocardial dysfunction was prevented in CARD9 knockout mice, with preserved cardiac function and cardiomyocyte contractility.
- CARD9 deficiency reduced macrophage infiltration in the heart and lowered levels of key pro-inflammatory cytokines.
- CARD9 knockout abrogated p38 MAPK phosphorylation increases, prevented LC3BII/LC3BI ratio decrease, and normalized p62 expression, restoring cardiac autophagy.
Conclusions:
- CARD9 knockout ameliorates myocardial dysfunction in high-fat diet-induced obesity.
- This protective effect is associated with reduced macrophage infiltration, suppressed p38 MAPK signaling, and preserved cardiac autophagy.
Abstract:
Obesity is associated with chronic inflammation which plays a critical role in the development of cardiovascular dysfunction. Because the adaptor protein caspase recruitment domain-containing protein 9 (CARD9) in macrophages regulates innate immune responses via activation of pro-inflammatory cytokines, we hypothesize that CARD9 mediates the pro-inflammatory signaling associated with obesity en route to myocardial dysfunction. C57BL/6 wild-type (WT) and CARD9(-/-) mice were fed normal diet (ND, 12% fat) or a high fat diet (HFD, 45% fat) for 5months. At the end of 5-month HFD feeding, cardiac function was evaluated using echocardiography. Cardiomyocytes were isolated and contractile properties were measured. Immunofluorescence was performed to detect macrophage infiltration in the heart. Heart tissue homogenates, plasma, and supernatants from isolated macrophages were collected to measure the concentrations of pro-inflammatory cytokines using ELISA kits. Western immunoblotting analyses were performed on heart tissue homogenates and isolated macrophages to explore the underlying signaling mechanism(s). CARD9 knockout alleviated HFD-induced insulin resistance and glucose intolerance, prevented myocardial dysfunction with preserved cardiac fractional shortening and cardiomyocyte contractile properties. CARD9 knockout also significantly decreased the number of infiltrated macrophages in the heart with reduced myocardium-, plasma-, and macrophage-derived cytokines including IL-6, IL-1β and TNFα. Finally, CARD9 knockout abrogated the increase of p38 MAPK phosphorylation, the decrease of LC3BII/LC3BI ratio and the up-regulation of p62 expression in the heart induced by HFD feeding and restored cardiac autophagy signaling. In conclusion, CARD9 knockout ameliorates myocardial dysfunction associated with HFD-induced obesity, potentially through reduction of macrophage infiltration, suppression of p38 MAPK phosphorylation, and preservation of autophagy in the heart.
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