MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction

Abstract

Heart disease remains a major complication of diabetes, and the identification of new therapeutic targets is essential. This study investigates the role of the protein kinase MK2, a p38 mitogen-activated protein kinase downstream target, in the development of diabetes-induced cardiomyopathy. Diabetes was induced in control (MK2(+/+)) and MK2-null (MK2(-/-)) mice using repeated injections of a low dose of streptozotocin (STZ). This protocol generated in MK2(+/+) mice a model of diabetes characterized by a 50% decrease in plasma insulin, hyperglycemia, and insulin resistance (IR), as well as major contractile dysfunction, which was associated with alterations in proteins involved in calcium handling. While MK2(-/-)-STZ mice remained hyperglycemic, they showed improved IR and none of the cardiac functional or molecular alterations. Further analyses highlighted marked lipid perturbations in MK2(+/+)-STZ mice, which encompass increased 1) circulating levels of free fatty acid, ketone bodies, and long-chain acylcarnitines and 2) cardiac triglyceride accumulation and ex vivo palmitate β-oxidation. MK2(-/-)-STZ mice were also protected against all these diabetes-induced lipid alterations. Our results demonstrate the benefits of MK2 deletion on diabetes-induced cardiac molecular and lipid metabolic changes, as well as contractile dysfunction. As a result, MK2 represents a new potential therapeutic target to prevent diabetes-induced cardiac dysfunction.

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

“…Nonetheless, future studies will likely reveal additional DACH1 targets in HCs that may shed additional light on gene expression changes in obesity. Finally, we recently published that drug-mediated inhibition of MK2, an enzyme linked to CaMKII in HCs in obesity, improves metabolism in obese mice (Ozcan et al, 2015), which is consistent with genetic studies conducted by our group (Ozcan et al, 2013) and an independent laboratory (Ruiz et al, 2015). Given that the upstream kinase pathway promotes diabetes by suppressing ATF6, the findings in this report provide important mechanistic underpinnings for future therapeutic strategies that attempt to improve metabolism in obese T2D subjects by targeting this pathway.…”

Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

“…For example, previous studies have shown that deletion of MAPK-activated protein kinase-2 (MK2), a downstream mediator of p38 MAPK, has benefits on ischaemiareperfusion and pressure overload-induced hypertrophy (Shiroto et al 2005, Streicher et al 2010. In recent findings, Ruiz and coworkers further demonstrated that deletion of Mk2 was associated with protection against STZ diabetes-induced cardiomyopathy (Ruiz et al 2016). Indeed, diabetic Mk2 −/− mice did not exhibit the elevated plasma-free FA levels, diastolic dysfunction, increased beta-Mhc/alpha-Mhc ratio, decreased SERCA2a levels or attenuated p38MAPK expression seen in Mk2 +/+ diabetic mice.…”

MK2-deficient mice are bradycardic and display delayed hypertrophic remodelling in response to a chronic increase in afterload

“…In addition, pharmacological inhibition of MK2 reduces cardiac fibrosis and preserves cardiac function following myocardial infarction (Xu et al, 2014). Finally, we have recently shown that the absence of MK2 prevents diabetes-induced cardiac dysfunction and perturbations in lipid metabolism (Ruiz et al, 2016;Ruiz et al, 2018).…”

“…Immunoblotting SDS-PAGE and immunoblotting were performed as described previously (Ruiz et al, 2016) with a slight modification. Following electrophoretic transfer to 0.22 µm nitrocellulose, membranes were rinsed in PBS and fixed with glutaraldehyde (Connern & Halestrap, 1996) prior to blocking.…”