Impaired Oxidative Stress Response in Right Ventricular Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) is a growing clinical entity and major health burden characterized by comorbid diabetes mellitus and heart failure. DCM has been commonly associated with impaired function of the left ventricle (LV); however, DCM likely also occurs in the right ventricle (RV), which has distinct physiology and pathophysiology from the LV. Indeed, we recently demonstrated fibrotic and hypertrophic remodeling of the RV alongside impaired RV systolic function in a mouse model of type II diabetes mellitus (T2DM). In diabetes, metabolic and mitochondrial perturbations lead to oxidative stress, contributing to cardiac dysfunction. The mechanisms by which the LV and RV respond to oxidative stress are distinct, with the RV having a significantly diminished ability to respond to stress compared to the LV. Here, we show that in a mouse model of T2DM, while the LV upregulates antioxidant defenses in response to diabetes, there is an absence of robust increase in antioxidant gene expression in the RV. Instead, the T2DM RV downregulates expression of manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme. Overexpression of MnSOD has been shown to alleviate oxidative stress in the LV, but it is unknown what impact MnSOD has in the diabetic RV. We hypothesized that lack of MnSOD upregulation in the RV contributes to oxidative stress and RV diabetic myopathy. To test this hypothesis, we developed a genetic model of inducible cardiac-specific MnSOD loss of function in the setting of T2DM. Ongoing work will comprehensively quantify RV function and metabolic and molecular phenotyping and perform extensive quantification of oxidative damage in this model, with the goal of elucidating RV- centric mechanisms involved in diabetic cardiomyopathy. Identifying these mechanisms is critical for the development of targeted treatments diabetic RV dysfunction. NIH R56HL164328 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.