Potential target to combat diabetic cardiomyopathy

Some patients with diabetes develop a serious disease known as diabetic cardiomyopathy, which is slow-moving and cannot be directly attributed to hypertension or other cardiovascular disorders. It is an alteration in cardiac function—often underdiagnosed—that is one of the main causes of death in diabetic patients and affects cases of type 1 and 2 diabetes. For now, no pharmacological treatment has yet been approved. specific clinical protocol to combat the disease.

A new study has managed to describe a potential target that could drive the design of new therapeutic strategies to specifically treat diabetic cardiomyopathy. The research exposes the beneficial effects that the activation of a protein—the nuclear receptor PPARbeta/delta—has on the disease, present in all cells of the body 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 Faculty of Pharmacy and Food Sciences of the University of Barcelona (UB), the Institute of Biomedicine of the UB (IBUB) and the Sant Joan de Déu Research Institute (IRSJD) in Barcelona, ​​direct the research as experts from the Networked Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), in Spain.

The new work is also signed by Adel Rostami from the UB; Fátima Crispi, from the UB and the Network Biomedical Research Center for Rare Diseases (CIBERER); Francisco Nistal, from the University of Cantabria and the Marqués de Valdecilla University Hospital and the Network Biomedical Research Center for Cardiovascular Diseases (CIBERCV), in Spain; and Walter Wahli, of the University of Lausanne in Switzerland, and other experts.

Adel Rostami and Manel Vázquez-Carrera, two of the authors of the study. (Photo: University of Barcelona. CC BY)

A protein involved in cardiac pathologies

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

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

«Many of the genes regulated by PPARbeta/delta are involved in lipid and glucose metabolism. This protein is related to metabolic diseases with an inflammatory background: for example, insulin resistance induced by obesity or diabetes, dyslipidemia or metabolic fatty liver disease (MASLD)”, details Professor Manuel Vázquez-Carrera.

«The majority of these pathologies are associated with a decrease in the transcriptional activity of PPARbeta/delta 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 involved in the development of several cardiac disorders,” says Vázquez-Carrera. “In parallel, it also has an important role in regulating inflammation and tissue remodeling.”

Inflammation, fibrosis and diabetic cardiomyopathy

In diabetes or obesity, insulin resistance in the myocardium determines that the heart obtains energy almost exclusively from the mitochondrial oxidation of fatty acids. This causes an accumulation of lipids in the myocardium and generates lipotoxicity, which results in an even greater demand for oxygen by the cardiac muscle. 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 cardiac remodeling process, which increases myocardial stiffness and alters the ability of the heart to relax (diastole) after contraction (systole).

Activation of NF-қB and AP-1, together with the activity of mitogen-activated protein kinases (MAPK), induces cell death of cardiomyocytes, which also contributes to contractile dysfunction in diabetic cardiomyopathy. Professor Xavier Palomer indicates that “together, all these processes give rise to extracellular cardiac remodeling, contractile dysfunction, left ventricular hypertrophy and dilated cardiomyopathy, which ultimately lead to heart failure.”

How does the PPARbeta/delta protein act in diabetic cardiomyopathy?

Until now, it was known that activation of PPARbeta/delta in the heart could prevent metabolic deregulation during diabetes and obesity. This would help avoid heart failure, that is, the inability of the heart to pump blood efficiently to all the organs and tissues of the body. As the new study reveals, the beneficial effect of the PPARbeta/delta protein in diabetic cardiomyopathy is explained by its ability to inhibit the MAPK pathway, according to the results obtained in human cardiac cells in culture.

Likewise, it was known that oxidative stress, hyperglycemia and lipotoxicity accelerate inflammation, fibrosis and apoptosis of cardiomyocytes in diabetic cardiomyopathy through the activation of mitogen-activated protein kinases (MAPK), which also affects tissue remodeling after myocardial infarction.

Vázquez-Carrera highlights 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.

In search of new treatments for patients

In August 2024, the U.S. Food and Drug Administration (FDA) approved the use of a new selective PPARbeta/delta agonist known as seladelpar to treat primary biliary cholangitis, a rare, chronic disease that affects the bile ducts. and can cause serious liver damage. Since February, the application for authorization for its marketing in the European Union has been under review.

“In this global health scenario, one might think that pharmaceutical companies could have increasing interest in the research and development of this type of drugs for the treatment of diabetic cardiomyopathy,” the researchers conclude.

The study is titled “PPARβ/δ prevents inflammation and fibrosis during diabetic cardiomyopathy.” And it has been published in the academic journal Pharmacological Research. (Source: University of Barcelona)