Abstract: SA-PO268
Adenine Is a Marker and Potential Driver of Heart Failure in Cardiovascular-Kidney-Metabolic Syndrome
Session Information
- Diabetic Kidney Disease: Basic - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Tamayo, Ian M., Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas, United States
- Lee, Hak Joo, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas, United States
- Trevino, Esmeralda, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas, United States
- Maity, Soumya, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas, United States
- Montellano, Richard, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas, United States
- Lim, Su-chi, Clinical Research Unit, Khoo Teck Puat Hospital,, Khoo Teck Puat, Singapore
- Lanzer, Jan D., Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany
- Iyengar, Ravi, Department of Pharmacological Sciences and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Bjornstad, Petter, Division of Nephrology, Department of Medicine and Section of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Tuttle, Katherine R., Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, United States
- Ramachandran, Vasan S., Division of Cardiology, University of Texas Health San Antonio, San Antonio, Texas, United States
- Abdel-Latif, Ahmed, Department of Medicine, University of Michigan, Ann Arbor, Michigan, United States
- Saez-Rodriguez, Julio, Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany
- Bopassa, Jean C., Department of Cellular and Integrative Physiology, University of Texas Health San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas, United States
Background
Cardiovascular-kidney-metabolic syndrome (CKM) is a risk factor for heart failure following the onset of diabetic kidney disease (DKD). Prior work identified a role for endogenous adenine in progressive DKD and urinary adenine to be predictive for progression. However, the underlying metabolic pathways of CKM are unknown.
Methods
Mass spectrometry imaging (MSI) and bulk tissue LC-MS were performed on human hearts from healthy and diabetic donors with left ventricular hypertrophy (LVH) (n = 5-6 per group). Sc-RNA-seq results from patient hearts with heart failure were analyzed for cell-specific changes in methylthioadenosine phosphorylase (MTAP) which produces adenine. Urinary adenine was measured in 661 participants with DKD as part of the Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), which tracked incident heart failure over a 10-year period. In addition, heart tissues from both a db/db diabetic mouse model (n=6 per group) and a high fat with L-NAME-treatment mouse model of heart failure (n=4-6 per group) were studied.
Results
In human hearts, MSI revealed an increase in adenine in coronary blood vessels from diabetics with LVH and was correlated with total heart weight. Sc-RNA-seq showed cardiac endothelial cells increase MTAP expression during heart failure. Results from the SMART2D studies show urinary adenine improves prediction of heart failure among DKD patients (unadjusted HR 1.54, 95% CI 1.15-2.05, adjusted 1.56, 95% CI 1.13-2.16). In the HFD+L-NAME mice heart tissues, vascular adenine and MTAP gene expression were increased. In db/db mice, urinary adenine correlated with heart adenine expression. Also, inhibition of MTAP in mice reduced urinary and vascular heart adenine, reduced heart size, and improved echocardiogram function.
Conclusion
Patients with CKM syndrome face a risk for both heart and kidney disease. MSI of human and mouse heart tissue revealed adenine to be localized to coronary blood vessels and intervention studies demonstrate a key role for adenine to mediate diabetic heart dysfunction. Taken together, adenine presents as a potentially actionable target in treatment of CKM syndrome.
Funding
- Other NIH Support