Mixed Lineage Kinase 3 mediates PKG1α impact on cardiac function and controls blood pressure through separate mechanisms

Abstract Chronic heart failure (CHF) is the final outcome of many cardiovascular diseases, and is a severe health issue faced by the elderly population. Mixed lineage kinase 3 (MLK3), a member of MAP3K family, is associated with aging, inflammation, oxidative stress, and related diseases, such as CHF. MLK3 has also been reported to play an important role in protecting against cardiomyocyte injury; however, its function in myocardial fibrosis is unknown. To investigate the role of MLK3 in myocardial fibrosis, we inhibited the expression of MLK3, and examined cardiac function and remodeling in TAC mice. In addition, we assessed the expression of MLK3 protein in ventricular cells and its downstream associated protein. We found that MLK3 mainly regulates NF-κB/NLRP3 signaling pathway-mediated inflammation and that pyroptosis causes myocardial fibrosis in the early stages of CHF. Similarly, MLK3 mainly regulates the JNK/p53 signaling pathway-mediated oxidative stress and that ferroptosis causes myocardial fibrosis in the advanced stages of CHF. We also found that promoting the expression of miR-351 can inhibit the expression of MLK3, and significantly improve cardiac function in mice subjected to TAC. These results suggest the pyroptosis and ferroptosis induced by MLK3 signaling in cardiomyocytes are essential for adverse myocardial fibrosis, in response to pressure overload. Furthermore, miR-351, which has a protective effect on ventricular remodeling in heart failure caused by pressure overload, may be a key target for the regulation of MLK3.

Download Full-text

Mixed Lineage Kinase 3 Regulates Blood Pressure through Kinase Independent Effects in the Vasculature

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2019.07.041 ◽

2019 ◽

Vol 25 (8) ◽

pp. S13-S14

Author(s):

Timothy D. Calamaras ◽

Robert A.U. Baumgartner ◽

Mark Aronovitz ◽

Joseph McCarthy ◽

Kelly Tam ◽

...

Keyword(s):

Blood Pressure ◽

Mixed Lineage Kinase ◽

Independent Effects ◽

Mixed Lineage Kinase 3

Download Full-text

Abstract 315: The Role of Mixed Lineage Kinase 3 in Inflammatory Cell-Fibroblast Communication

Circulation Research ◽

10.1161/res.115.suppl_1.315 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Emily M Schulz ◽

Allison E Dixon ◽

Michael S Burhans ◽

Michelle L Nieman ◽

John N Lorenz ◽

...

Keyword(s):

Inflammatory Response ◽

Cardiac Function ◽

Inflammatory Cell ◽

Cardiac Fibroblasts ◽

Systolic Pressure ◽

Mitogen Activated Protein Kinase ◽

Positive Staining ◽

Mixed Lineage Kinase ◽

Mixed Lineage Kinase 3

Mixed lineage kinase 3 (MLK3) is a ubiquitously expressed pro-inflammatory, pro-apoptotic mitogen activated protein kinase kinase kinase (MAP3K). MLK3 is a key regulator of the p38 and c-jun terminal kinase (JNK) pathways and has been studied in cancer and neurodegenerative disease. Although the p38 and JNK pathways have been studied in the cardiac function and disease, little is known regarding the role of MLK3 in the heart. Studies in our laboratory have indicated that MLK3 RNA is highly expressed in macrophages, cardiomyocytes and cardiac fibroblasts, suggesting an important role in cardiac function. Recently published work has indicated that MLK3 plays an important role in inflammatory cell motility, leading us to hypothesize that MLK3 is involved in inflammatory cell-fibroblast communication during cardiac disease. Knockout (KO) or inhibition of MLK3 using the novel small molecule inhibitor URMC-099 does not significantly affect heart rate, mean arterial pressure, systolic pressure, minimum or maximum dp/dt compared to wild type (WT) controls as measured by invasive hemodynamics at 3 months of age. Echocardiographic analysis indicates that MLK3 KO or inhibition does not affect cardiac architecture or cardiac function, indicated by fractional shortening or ejection fraction. However, upon transaortic constriction (TAC), MLK3 KO and URMC-099 treatment results in decreases in Mac-3 positive staining at 3 and 7 days post-TAC as well as decreases in CD-45 staining 7 days post-TAC compared to WT TAC operated, vehicle treated controls, suggesting that MLK3 KO and drug treatment may attenuate the early inflammatory response after TAC. Studies examining the relationship between the MLK3 mediated inflammatory response and subsequent fibrosis and cardiac dysfunction post-TAC are currently ongoing.

Download Full-text

Faculty Opinions recommendation of The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718021750.793479022 ◽

2013 ◽

Author(s):

Anirban Basu ◽

Deepak Kaushik

Keyword(s):

Human Immunodeficiency Virus ◽

Small Molecule ◽

Neurocognitive Disorders ◽

Mixed Lineage Kinase ◽

Immunodeficiency Virus ◽

Anti Inflammatory ◽

Mixed Lineage Kinase 3

Download Full-text

The Copenhagen chronic kidney disease echo study (COInCYDE)

European Heart Journal ◽

10.1093/ehjci/ehaa946.3326 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

N Landler ◽

S Bro ◽

B Feldt-Rasmussen ◽

D Hansen ◽

A.L Kamper ◽

...

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Cohort Study ◽

Kidney Disease ◽

Cardiac Function ◽

Left Ventricular ◽

Funding Source ◽

Ckd Stage ◽

Significant Difference ◽

Stage 1

Abstract Background The cardiovascular mortality of patients with chronic kidney disease (CKD) is 2–10 times higher than in the average population. Purpose To estimate the prevalence of abnormal cardiac function or structure across the stages CKD 1 to 5nonD. Method Prospective cohort study. Patients with CKD stage 1 to 5 not on dialysis, aged 30 to 75 (n=875) and age-/sex-matched controls (n=173) were enrolled consecutively. All participants underwent a health questionnaire, ECG, morphometric and blood pressure measurements. Blood and urine were analyzed. Echocardiography was performed. Left ventricle (LV) hypertrophy, dilatation, diastolic and systolic dysfunction were defined according to current ESC guidelines. Results 63% of participants were men. Mean age was 58 years (SD 12.6 years). Mean eGFR was 46.7 mL/min/1,73 m (SD 25.8) for patients and 82.3 mL/min/1,73 m (SD 13.4) for controls. The prevalence of elevated blood pressure at physical exam was 89% in patients vs. 53% in controls. Patients were more often smokers and obese. Left ventricular mass index (LVMI) was slightly, albeit insignificantly elevated at CKD stages 1 & 2 vs. in kontrols: 3.1 g/m2, CI: −0.4 to 6.75, p-value 0.08. There was no significant difference in LV-dilatation between patients and controls. Decreasing diastolic and systolic function was observed at CKD stage 3a and later: LVEF decreased 0.95% (CI: −1.5 to −0.2), GLS increased 0.5 (CI: 0.3 to 0.8), and OR for diastolic dysfunction increased 3.2 (CI 1.4 to 7.3) pr. increment CKD stage group. Conclusion In accordance to previous studies, we observe in the CPHCKD cohort study signs of early increase of LVMI in patients with CKD stage 1 & 2. Significant decline in systolic and diastolic cardiac function is apparent already at stage 3 CKD. Figure 1. Estimated GFR vs. GLS & histogram of GLS Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): The Capital Region of Denmark

Download Full-text