A new study reveals that activating the nuclear receptor PPARß/d could offer therapeutic potential for diabetic cardiomyopathy, a severe cardiac condition affecting both type 1 and type 2 diabetes patients, which currently lacks specific treatment options.
Identifying the therapeutic pathway
Research published in the November 2024 issue of Pharmacological Research has identified a promising molecular target for treating diabetic cardiomyopathy. The study, led by researchers at the University of Barcelona, demonstrates that activation of the nuclear receptor PPARß/d may help counteract the inflammatory and fibrotic processes characteristic of this cardiac condition.
Diabetic cardiomyopathy represents a significant health burden, particularly as it develops insidiously and cannot be directly attributed to hypertension or other cardiovascular disorders. The condition is characterised by complex pathological processes including metabolic alterations, inflammation, fibrosis, and cardiac cell death through apoptosis.
The research team found that the PPARβ/δ receptor, which is particularly abundant in metabolically active tissues, can potentially mitigate disease progression. “Many of the PPARβ/δ-regulated genes are pharmainvolved in lipid and glucose metabolism. This protein is linked to metabolic diseases with an inflammatory background,” explains Professor Manuel Vázquez-Carrera, one of the study’s lead researchers.
Molecular mechanisms unveiled
In diabetic conditions, insulin resistance in the myocardium forces the heart to rely almost exclusively on fatty acid oxidation for energy production. This metabolic shift leads to lipid accumulation and subsequent lipotoxicity, increasing the heart’s oxygen demands. The combination of diabetic hyperglycaemia and lipo-toxicity triggers inflammatory and fibrotic responses through the activation of specific transcription factors.
Professor Xavier Palomer, co-lead researcher, explains: “Together, all these processes lead to extracellular cardiac remodelling, contractile dysfunction, left ventricular hypertrophy and dilated cardiomyopathy, ultimately leading to heart failure.”
Clinical implications and future directions
The study’s fndings are particularly relevant given recent developments in PPARβ/δ-targeted therapeutics. In August 2024, the US FDA approved seladelpar, a selective PPARβ/δ agonist, for treating primary biliary cholangitis. This regulatory milestone could accelerate interest in developing similar compounds for diabetic cardiomyopathy. The research reveals that PPARβ/δ’s beneficial effects in diabetic cardiomyopathy stem from its ability to inhibit the MAPK pathway, as demonstrated in cultured human cardiac cells. This mechanism appears to be crucial in preventing inflammation and fibrosis not only in cardiac tissue but potentially in other organs affected by similar pathological conditions.
Therapeutic potential
The study’s fndings suggest that pharmaceutical companies might increasingly focus on developing PPARβ/δ-targeted drugs for diabetic cardiomyopathy treatment. This development is particularly significant given the current lack of specific therapeutic options for this serious cardiac condition.
The research team included collaborators from BCNatal, Hospital Clínic IDIBAPS, the University of Cantabria, Marqués de Valdecilla University Hospital, and the University of Lausanne, representing a comprehensive international effort to address this challenging medical condition.
Reference:
Rostami, A., Palomer, X., et al. (2024). PPARß/d prevents inflammation and fibrosis during diabetic cardiomyopathy. Pharmacological Research. https://doi.org/10.1016/j.phrs.2024.107515
