Diabetic Cardiomyopathy: An Immunometabolic Perspective

Abstract

The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM. These early events are followed by steatosis (accumulation of lipid droplets) in cardiomyocytes, which is followed by apoptosis, changes in immune responses with a consequent increase in fibrosis, remodeling of cardiomyocytes, and the resultant decrease in cardiac function. The heart is an omnivore, metabolically flexible, and consumes the highest amount of ATP in the body. Altered myocardial substrate and energy metabolism initiate the development of DCM. Diabetic hearts shift away from the utilization of glucose, rely almost completely on fatty acids (FAs) as the energy source, and become metabolically inflexible. Oxidation of FAs is metabolically inefficient as it consumes more energy. In addition to metabolic inflexibility and energy inefficiency, the diabetic heart suffers from impaired calcium handling with consequent alteration of relaxation-contraction dynamics leading to diastolic and systolic dysfunction. Sarcoplasmic reticulum (SR) plays a key role in excitation-contraction coupling as Ca²⁺ is transported into the SR by the SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a) during cardiac relaxation. Diabetic cardiomyocytes display decreased SERCA2a activity and leaky Ca²⁺ release channel resulting in reduced SR calcium load. The diabetic heart also suffers from marked downregulation of novel cardioprotective microRNAs (miRNAs) discovered recently. Since immune responses and substrate energy metabolism are critically altered in diabetes, the present review will focus on immunometabolism and miRNAs.

Keywords: cardiomyopathy; fat metabolism; glucose metabolism; inflammation; innate and adaptive immunity; insulin resistance; miRNA; obesity.

Figure 1

Schematic diagram showing changes in cardiac metabolism in diabetic cardiomyopathy. In the diabetic heart, glucose oxidation is inhibited at multiple steps: (i) uptake of glucose is inhibited by reduced expression of glucose transporter Glut4 as well as by blunted translocation of Glut4 in response to insulin (64, 65); (ii) inhibition of hexokinase activity by fatty acids (FAs) resulting in reduced conversion of glucose to glucose-6-phosphate (80); (iii) inhibition of phosphofructokinase activity by FA, leading to reduced formation of fructose-1,6-bisphosphate by fructose-6-phosphate (69); (iv) inhibition of pyruvate dehydrogenase phosphatase activity by FA resulting in reduced pyruvate dehydrogenase (PDH) activity, which leads to reduced conversion of pyruvate to acetyl CoA. In the diabetic heart, PPARα expression is activated by increased FA uptake (81, 82). Activated PPARα upregulates PDH kinase 4 enzymes, which inhibits PDH resulting in reduced production of acetyl CoA (–85). FA transporters CD36 and FA transport protein import FAs into the cell. After import, FAs can be stored as triacylglycerol (TAG) or converted to fatty acyl CoA by fatty acyl-CoA synthetase (FACS). Carnitine palmitoyltransferase 1 (CPT1) transfers the acyl group of fatty acyl CoA to carnitine, which then shuttles into the mitochondria by carnitine translocase (CT). PPARα activates transcription of CPT1 (86). In the matrix, CPT2 reconverts the acylcarnitine back into free carnitine and fatty acyl CoA (87), which is then converted to acetyl CoA that can be used in the tricarboxylic acid to produce adenosine triphosphate by β-oxidation. Diabetes upregulates mitochondrial generation of reactive oxygen species (57, 88, 89), which affects Ca²⁺ signaling (90).

Figure 2

(A) Schematic diagram showing immune cells in the healthy heart. Macrophages are the preponderant immune cells in the resting heart and reside primarily surrounding endothelial cells and also in the interstitium among cardiomyocytes (–143). The less preponderant immune cells include the following: mast cells, dendritic cells, B cells, and regulatory T (T_Reg) cells (142, 144, 147). Neutrophils and monocytes, in general, are not detected in the resting heart. (B) Schematic diagram showing infiltration of neutrophils and monocytes from the circulation and their effects on resident immune cells in the diabetic cardiomyopathy (DCM) heart. In DCM, activated B cells release CCL7 that activates blood monocytes (146). Upon infiltration activated monocytes stimulate mast cells to release histamine, TNF, and interleukin 1β (IL1β), which activate neutrophils in circulation (144, 174). Activated neutrophils infiltrate heart and activate mast cells through damage-associated molecular patterns as well as blood neutrophils. Activated monocytes secrete TGFβ, which activates fibroblasts to induce formation of collagen.