[R01] Understanding how SGLT2 inhibitors protect from heart failure
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-01-31
Importo max: 765.129 EUR
Paese: US
Descrizione
SUMMARY
Heart failure is a leading cause of death worldwide, and the leading cause of hospital admissions in patients
over 65 in the US. The role of metabolism in cardiac pathology has long been of interest, but no therapies that
target cardiac metabolism are known. Recently, Na+/glucose transporter 2 inhibitors (SGLT2i), originally
designed as therapies for diabetes, have taken HF management by storm, demonstrating 20-30% reductions in
heart failure hospitalizations in large phase III trials, even in patients without diabetes. How SGLT2i confer
these benefits remains a mystery. In extensive preliminary data, we now show that SGLT2i directly activate
pantothenate kinase (PANK), the first and rate-limiting enzymatic step in the synthesis of co-enzyme A (CoA)
from pantothenate (vitamin B5). CoA is an obligate intracellular metabolite critical for most oxidative processes,
especially in highly oxidative tissues like the heart. We show in our preliminary data SGLT2i directly promote
cardiac CoA synthesis and oxidative metabolism, and promote cardiomyocyte contractility. Together our data
lead us to hypothesize that:
SGLT2i confer benefit in heart failure by activating PANK and boosting cardiac CoA metabolism.
We will test this hypothesis in depth by:
Aim 1: Understand the consequences of SGLT2i on cardiac CoA metabolism and fuel use.
Aim 2: Test in vivo the role of cardiac PANK in the heart failure protection conferred by SGLT2i.
Aim 3: Identify the molecular mechanism of activation of PANK by SGLT2i.
Aim 4: Begin a discovery campaign of novel small molecules to target PANK but not SGLT2.
These highly focused studies will elucidate how SGLT2i target PANK, and in turn protect from heart failure.
Precise structural and physiological understanding of how SGLT2i target PANK will enable design of small
molecules that improve on SGLT2i efficacy and reduce the side effects of SGLT2i. Success in these studies will
thus potentially open the door for the generation of entirely new classes of drugs to treat heart failure.
Istituzione: UNIVERSITY OF PENNSYLVANIA
PI: Zoltan P Arany
Progetto: 1R01HL183880-01
Settori: National Heart Lung and Blood Institute
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