New target for diabetic heart disease therapy

 Some patients with diabetes develop a serious condition known as diabetic cardiomyopathy, which proceeds slowly and cannot be directly attributed to hypertension or other cardiovascular disorders. This often under-diagnosed heart function impairment is one of the leading causes of death in diabetic patients and it affects both type 1 and type 2 diabetics. There is no current specific drug treatment or clinical protocol approved to address this disease.

A study published in the journal Pharmacological Research describes a potential target that could spur the design of new therapeutic strategies to specifically treat diabetic cardiomyopathy.

The paper describes the beneficial effects on the disease of activating a protein—the nuclear receptor PPARβ/δ—present in all body cells and especially abundant in organs and tissues with more active metabolism (skeletal muscle, heart, liver or adipose tissue).

Manuel Vázquez-Carrera and Xavier Palomer, from the UB's Faculty of Pharmacy and Food Sciences, the UB Institute of Biomedicine (IBUB) and the Sant Joan de Déu Research Institute (IRSJD), led the study as experts from the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Center (CIBERDEM).

Other researchers on this paper are Fátima Crispi, from the UB's Faculty of Medicine and Health Sciences, BCNatal (IRSJD and Hospital Clínic—IDIBAPS) and the Center for Biomedical Research Network on Rare Diseases (CIBERER); Francisco Nistal, from the University of Cantabria and the Marqués de Valdecilla University Hospital and the Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), and Walter Wahli, from the University of Lausanne (Switzerland), among other experts.

A protein involved in cardiac pathologies

Alterations in metabolism, inflammation, fibrosis and cardiac cell death by apoptosis are some of the causes for the development of diabetic cardiomyopathy. The study reveals that activation of the PPARβ/δ receptor can help to slow down the processes of inflammation and fibrosis in laboratory animal models and human cardiac cells under hyperglycemic conditions.

The PPARβ/δ factor is the most abundant member of the peroxisome proliferator-activated receptor (PPAR) family in the heart. However, Vázquez-Carrera notes that "the energy reservoir it contains is barely sufficient to maintain cardiac function for more than 10 seconds, a constant supply of energy obtained through the oxidation of fatty acids (70%) and, to a lesser extent, other substrates such as glucose or lactate, supplied through the blood."

"Most of these pathologies are associated with a decrease in the transcriptional activity of PPARβ/δ and, in fact, it has been suggested that its activation could be useful to treat them. A reduction in the activity of this protein is also implicated in the development of several cardiac disorders," says Vázquez-Carrera. "It also plays an important role in the regulation of inflammation and tissue remodeling," he adds.

Inflammation, fibrosis and diabetic cardiomyopathy

In diabetes or obesity, insulin resistance in the myocardium causes the heart to derive energy almost exclusively from mitochondrial oxidation of fatty acids. This causes lipid accumulation in the myocardium and leads to lipotoxicity, which results in the heart muscle demanding more oxygen.

Diabetic hyperglycemia and lipotoxicity trigger cardiac inflammation and fibrosis through the activation of proinflammatory and profibrotic transcription factors (NF-қB and AP-1). Once activated, these factors drive the process of cardiac remodeling, which increases myocardial stiffness and impairs cardiac relaxation (diastole) after contraction (systole).

The activation of NF-қB and AP-1, together with mitogen-activated protein kinase (MAPK) activity, induces cardiomyocyte cell death, which also contributes to contractile dysfunction in diabetic cardiomyopathy. Professor Palomer points out that "together, all these processes lead to extracellular cardiac remodeling, contractile dysfunction, left ventricular hypertrophy and dilated cardiomyopathy, ultimately leading to heart failure."

How does the PPARβ/δ protein act

To date, it was known that activation of PPARβ/δ in the heart could prevent metabolic dysregulation during diabetes and obesity. This would help prevent heart failure, the inability of the heart to pump blood efficiently to all organs and tissues in the body.

The study reveals that the beneficial effect of the PPARβ/δ protein in diabetic cardiomyopathy is explained by its ability to inhibit the MAPK pathway, according to the results obtained in cultured human cardiac cells.

Oxidative stress, hyperglycaemia and lipotoxicity were also known to accelerate cardiomyocyte inflammation, fibrosis and apoptosis in diabetic cardiomyopathy through the activation of mitogen-activated protein kinases (MAPKs), which also affects tissue remodeling after myocardial infarction.

Vázquez-Carrera points out that "it is not surprising, therefore, that the inhibition of these MAPKs can prevent inflammation and fibrosis not only in the heart, but also in other organs and tissues such as the liver, lung, kidney or even skeletal muscle, in various pathological conditions."

Searching for new treatments

In August 2024, the US Food and Drug Administration (FDA) approved the use of a new selective PPARβ/δ agonist known as seladelpar to treat primary biliary cholangitis, a rare, chronic disease that affects the bile ducts and can cause severe liver damage. As of February, the application for marketing authorization in the European Union is under review.

"In this global health scenario, it might be thought that pharmaceutical companies could be increasingly interested in the research and development of such drugs for the treatment of diabetic cardiomyopathy," the researchers conclude.