Cardiac Microvascular Dysfunction and Cardiomyopathy in Diabetes: Is Ferroptosis a Therapeutic Target? Free

Type 2 diabetes (T2D) accelerates coronary artery disease and predisposes patients to cardiomyopathy and heart failure. Numerous studies have examined the potential mechanisms underpinning the pathogenesis of cardiomyopathy and heart failure in diabetes over the past several decades. While the exact mechanisms remain elusive, glucose toxicity, lipotoxicity, mitochondrial dysfunction, oxidative stress, inflammation, and many other factors have been implicated as causative (1). In this issue of Diabetes, Chen et al. (2) present important studies describing mechanisms by which T2D and glucolipotoxicity engender cardiac microvascular structural and functional abnormalities via mitochondrion-derived ferroptosis signaling. The findings clearly demonstrate a causative role of ferroptosis in cardiac microvascular endothelial dysfunction in db/db diabetic mice and, thus, may have important implications for the pathophysiology of diabetic cardiomyopathy as well as for the development of effective therapeutics in the future.

Ferroptosis, first reported in 2012, is programmed, iron-dependent, nonapoptotic cell death via phospholipid peroxidation (3). The process relies on ferrous iron (Fe²⁺), reactive oxygen species, and phospholipids containing polyunsaturated fatty acid chains and is enhanced by the accumulation of lipid peroxides in the membrane system due to Fe²⁺-mediated Fenton reactions and reactive oxygen species (4). Under normal physiology, the cellular antioxidant system neutralizes lipid peroxidation with glutathione peroxidase 4 (GPX4), a selenoenzyme that selectively neutralizes lipid hydroperoxides and a key inhibitor of phospholipid peroxidation and thus ferroptosis. Patients with diabetes and hyperglycemia have significantly reduced GPX4 enzyme in their hearts compared with age-matched patients without diabetes (5). Peroxiredoxin-2 (PRDX2) is a redox-sensitive, thiol-specific peroxidase that protects cells against oxidative stress, is highly expressed in endothelial cells in atherosclerotic lesions, and inhibits atherogenic responses in vascular and inflammatory cells (6). The findings by Chen et al. (2), namely, that PRDX2 expression was decreased in cardiac microvascular endothelial cells and that endothelium-specific overexpression of PRDX2 alleviated cardiac microvascular injury and improved cardiac function in db/db mice, restored GPX4 expression, reduced Fe²⁺ load, and reduced lipid peroxidation accumulation in cardiac microvascular endothelial cells, support a cogent argument for a contributory role of cardiac endothelial injury to the development of cardiomyopathy and implicate endothelial cell ferroptosis as an intervention target for preventing and/or reversing cardiomyopathy associated with diabetes.

Multiple studies have suggested ferroptosis as a therapeutic target for cardiomyopathy in individuals with or without diabetes. Ferroptosis promotes atherosclerosis by accelerating endothelial dysfunction (7), and inhibition of ferroptosis could reduce atherosclerosis through attenuating endothelial cell lipid peroxidation (8). Ferroptosis mediates chemotherapy- and ischemia/reperfusion-induced cardiomyopathy, which could be alleviated either by iron chelation or inhibition of ferroptosis in mice (9). Additionally, ferroptosis appears to be involved in the pathogenesis of diabetic nephropathy, as evidenced by reduced GPX4 expression in kidney samples from patients or mice with diabetes, decreased mouse kidney glutathione concentrations, increased lipid peroxidation in mouse kidneys, and, most importantly, diminution of these changes by ferrostatin-1, a potent and selective inhibitor of ferroptosis treatment (10).

The cardiac microvasculature plays a pivotal role in maintaining the health and function of the heart. It provides endothelial surface area to facilitate the delivery of oxygen, nutrients, and hormones to and removal of metabolic end products from cardiomyocytes. In heart, ∼90% of the blood volume is located in the microvascular compartment within the myocardium (11), and only ∼50% of myocardial capillaries are being perfused at rest (12). The coronary circulation oxygen extraction is nearly maximal at rest, and when the myocardial demand for oxygen increases, as seen during exercise, coronary blood flow increases via dilatation of coronary microvasculature and capillary recruitment to meet the need. Microvascular abnormalities, including structural abnormalities and functional aberrance, are clearly present in diabetic hearts (13). The morphological changes of small vessels include periarterial fibrosis, arteriolar thickening, focal constrictions, microvascular tortuosity, capillary basement membrane thickening, capillary microaneurysms, and decreased capillary density (14,15). Evidence of cardiac microvascular dysfunction includes a reduced coronary flow reserve and endothelium-dependent coronary vasodilation (16), a paradoxical decrease in microvascular perfusion after mixed-meal challenge (17), and a decreased flow reserve due to increased blood viscosity (18).

The importance of preventing or correcting cardiac microvascular abnormalities (both structural and functional) cannot be overemphasized, particularly in patients with T2D, as they frequently have fixed stenosis in major coronary arteries due to coronary atherosclerosis, which limits the total blood supply to the myocardium. In healthy hearts, myocardium possesses a large endothelial surface area, with endothelial cells outnumbering cardiomyocytes by 3 to 1, and each square millimeter of myocardium contains 3,000–4,000 capillaries that run parallel to cardiomyocytes (13). At rest, epicardial coronary blood flow remains normal until >85% of the lumen is blocked, but during hyperemia, total flow is reduced when the stenosis exceeds 50%. A reduction in cardiac microvascular perfusion under this circumstance would severely reduce the perfused capillaries and delivery of oxygen, nutrients, and hormones to myocardium and thus jeopardize myocardial health and function. This may explain why patients with T2D tend to develop cardiac complications including cardiomyopathy and heart failure, even in the absence of clinically evident coronary artery atherosclerosis. This also suggests that cardiac microvascular abnormalities are an inciting and perpetuating factor for the development of cardiomyopathy in diabetes, and the cardiac microvasculature might be an important therapeutic target for preventing or reducing cardiac morbidities associated with diabetes. Indeed, Chen et al. (2) found that isorhapontigenin, an orally bioavailable dietary polyphenol and resveratrol analog with potent antioxidant and anti-inflammatory properties, was able to prevent cardiac microvascular endothelial cell injury induced by glucolipotoxicity in vitro and lessen cardiac microvascular structural and functional abnormalities in diabetic db/db mice in vivo, and the latter was associated with improved cardiac function as assessed using echocardiography. It appears that isorhapontigenin exerted these salutary actions via inhibition of mitochondrion-derived ferroptosis through the PRDX2-MFN2-ACSL4 signaling pathway.

While Chen et al. (2) elegantly demonstrated a critical role of ferroptosis in cardiac microvascular dysfunction in diabetic db/db mice, linked the latter to myocardial dysfunction, and implicated cardiac microvascular endothelial cell ferroptosis as a therapeutic target for the prevention and possible reversal of cardiomyopathy in diabetes (Fig. 1), the study also brought up several important issues that must be addressed. First, the study findings have to be validated using other animal models of T2D, as db/db mice are characterized by leptin receptor mutation and exhibit severe obesity, insulin resistance, and T2D, and all these factors could affect ferroptosis signaling and the development of cardiac microvascular dysfunction. Second, isorhapontigenin treatment, similar to PRDX2 overexpression, increased cardiac microvascular density. On the other hand, resveratrol possesses possibly angiostatic actions, including lowering exercise training–induced angiogenesis in humans (19) and inhibiting endothelial cell proliferation and migration in vitro (20). Third, the use of FITC-lectin perfusion combined with the CD31 staining method to detect microvascular blood flow is less optimal, and more direct measurements, such as positron emission tomography imaging, MRI imaging, or myocardial contrast echocardiography, would provide more reliable evidence. We have previously shown in rodents that acute systemic administration of resveratrol increased microvascular perfusion in skeletal muscle. Finally, all experiments were done using male mice, and there is a lack of information on sex-specific differences. Until further evidence is obtained, the findings from this study should not be extrapolated to other animal models or humans. Nonetheless, the study results open an important new venue for the mechanistic studies of the pathogenesis of diabetic cardiomyopathy.