Heart failure (HF) is a leading cause of cardiovascular mortality and morbidity in the United States.
Despite current treatments, patients with HF suffer from a poor quality of life and reduced lifespan.
An improved understanding of the critical pathological mechanisms of HF is required for the
development of novel therapies. Hydrogen sulfide (H2S) is a potent endogenous, gaseous signaling
molecule that critically regulates cardiovascular homeostasis. H2S regulates blood pressure, inhibits
apoptosis and inflammation, protects mitochondria, and exerts powerful antioxidant actions. Previous
work from our group has shown that exogenously administered H2S produces robust
cardioprotective effects in animal models of heart failure. We have shown that gene-targeted mice
that overexpress endogenous H2S producing enzymes are protected in the setting of HF. H2S is
generated endogenously by three enzymes cystathionine ¿-lyase (CSE), cystathionine ß-synthase
(CBS) and 3-mercaptopyruvate sulfurtranseferase (3-MST). CSE, CBS and 3-MST are all expressed
in the heart and circulation, but exhibit significant differences in their regulation and cellular
localization. Our Central Hypothesis for the proposed studies is that H2S derived from different
enzymes, in different cell populations (endothelial cells, cardiac myocytes, fibroblasts) exerts
distinct cardioprotective effects in the pathogenesis of HF. Although, we have demonstrated
that H2S levels are reduced in the heart and circulation of both laboratory animals and patients with
heart failure, the causes and consequences of reduced H2S availability are poorly characterized. We
have developed novel gain and loss of function mouse models that will provide mechanistic insights
regarding the contribution of CSE, CBS and 3-MST to HF development and progression. We will
employ a multifaceted approach that includes physiological, molecular, biochemical, genetic, and
pharmacological approaches to elucidate the role of endogenous H2S in heart failure. The proposed
studies will evaluate left ventricular structure and function, cardiac fibrosis, exercise capacity,
vascular function, mitochondrial bioenergetics, and molecular signaling to evaluate the role of
endogenous H2S on the pathobiology of HF.
Specifically, we will: (1) determine the time course of expression of all three endogenous H2S
generating enzymes as well as the levels of H2S bioavailability in pressure overload and myocardial
infarction induced HF; (2) directly investigate the contribution of H2S-producing enzymes in the
development and progression of HF pathology through the use of cell type-specific gene-targeted
mouse models with gain and loss of function for CSE, CBS, and 3-MST; (3) identify novel
endogenous cytoprotective signal cascades mediated via endogenous H2S producing enzymes in
the early and late stages of pressure overload and MI induced HF.
Successful completion of these studies will further our understanding of the pathogenesis of HF and
will provide critical information required for the development of improved pharmacological strategies
to harness H2S therapy for the benefit of patients with HF.