Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent and complex syndrome for which no etiological therapy is available. Osteopontin (OPN) is a matricellular protein that induces mitochondrial damage and oxidative stress in cardiac myocytes. OPN is upregulated in the circulation of HFpEF patients. Our work and preliminary data show that the Col4a3-/- mice, a model of kidney disease, display a HFpEF phenotype that includes cardiac diastolic dysfunction, hypertrophy, fibrosis, hypertension, and elevated renal and plasma levels of OPN. Our preliminary data reveals that mRNA and protein levels of 2-Oxoglutarate Dehydrogenase- Like (OGDHL), a Krebs cycle isoenzyme involved in OGDH complex formation and mitochondrial energy metabolism, is decreased in Col4a3-/- hearts. We found that double knockout Col4a3-/-OPN-/- mice have elevated cardiac OGDHL protein levels, and improved HFpEF phenotype. Dysregulated myocardial energetics in HFpEF patients is known to be a major contributor to disease progression. Therefore, using small and large animal models of HFpEF, we will test the hypothesis that upregulated OPN, released from the kidney, activates pathological signaling in the heart causing a decline in OGDHL and related ATP production contributing to the observed HFpEF phenotype in Col4a3-/- mice.

Public Health Relevance

Due in part to the complex heterogeneity of the disease phenotypes as well as an absence of mechanistic insights into disease development and progression, clinical trials targeting heart failure with preserved ejection fraction (HFpEF) so far have failed and there is no etiological therapy for HFpEF. The current proposal will allow us to understand new mechanisms underlying the development of HFpEF, and provide new targets for treating HFpEF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL140468-03
Application #
9849803
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2018-02-01
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146