Determinants of cardioprotection by circulating prohibitin-1 during sepsis

ABSTRACT: Sepsis is a dangerous hyper-inflammatory condition that carries a mortality rate of 25% for
uncomplicated cases and rises to 80% for patients who develop multiple organ dysfunction syndrome (MODS).
No specific therapies for MODS exist, which is why identification of druggable targets and biomarkers for
diagnosis/prognosis are urgently needed. During the acute phase response in sepsis, circulating factors such
as cytokines and endotoxins cause oxidative stress and derangements in mitochondrial morphology and
function in the heart, ultimately leading to septic cardiomyopathy (SepCM), a manifestation of MODS.
Prohibitins (PHB1,2) are proteins that assemble in hetero-oligomeric complexes within the mitochondrial inner
membrane and in plasma membrane lipid rafts, where studies show they are at the nexus of many vital cellular
functions including metabolism, proliferation, oxidative stress and apoptosis. The current proposal stems from
our recent findings that PHB1 is a dynamic acute phase reactant protein in sepsis, and its secretion during
sepsis is abrogated in mice lacking the anti-inflammatory transcription factor Nrf2 (i.e., NFE2L2). Importantly,
bloodborne PHB1 is biologically active, as administration of recombinant human PHB1 (rPHB1) activates PI3K-
AKT signaling and enhances aerobic glucose oxidation and pentose phosphate pathway in the heart, and
preserves cardiac mitochondrial oxidative phosphorylation (OxPHOS) in mouse models of sepsis. We also
have very exciting preliminary evidence that serum PHB1 levels are associated with MODS and mortality in
sepsis patients. Experiments outlined in this proposal will test our central hypothesis that bloodborne PHB1 is a
stress-induced ‘hepatokine’ that mediates a liver-to-heart protective feedback signal during sepsis by
enhancing oxidative glucose metabolism (i.e. suppressing lactate production) and preserving mitochondrial
structure and function in the myocardium. This cardioprotective effect of circulating PHB1 can be
therapeutically exploited to treat SepCM.
Our established interdisciplinary team will test this hypothesis in three Aims. Work in Aim 1 will determine
the Nrf2-mediated mechanisms controlling PHB1 secretion in hepatocytes. In Aim 2 we will identify the
mechanisms of cardio-protection conferred by circulating PHB1 during sepsis. Work in Aim 3 will validate
serum PHB1 as a predictive biomarker of morbidity and mortality in a cohort of patients with established sepsis
(INVACS cohort, University of Utah). Each Aim is hypothesis-driven, and the work will be performed using
gain/loss-of-function approaches in primary cell culture, clinically relevant mouse models of severe sepsis, and
serum samples from a well-characterized cohort of sepsis patients. We will leverage the complementary and
uniquely distinct expertise of our research team to elucidate cardioprotective mechanisms of circulating PHB1,
and to exploit these mechanisms to treat a very serious and deadly clinical condition.

Grant Number: 5R01HL167087-04
NIH Institute/Center: NIH
Principal Investigator: Ethan Anderson