Biochemical Silencing of Maladaptive Inflammation in Heart Failure

Project Abstract Pathologic remodeling is a central feature of heart failure. Remodeling is characterized by oxidative stress and inflammation. Current pharmacological interventions only slow the progression of heart failure and do not target the underlying pathology. Thus, an innovative approach is needed to correct the underlying pathology and improve the function of failing hearts. Extensive work has shown the association between inflammation and cardiac remodeling; however, previous attempts to target inflammation in heart failure patients were ineffective. The harmful effects of oxidative stress are mediated by reactive aldehydes formed by the oxidation of lipid membranes. These reactive aldehydes possess two electrophilic moieties, which bind with proteins forming aldehyde-modified protein adducts. The free aldehydic groups within these modified proteins behave as aldehyde-modified damage associated molecular patterns (ADAMPs) and elicit adaptive immune responses. Extensive studies show ADAMPs are increasingly generated in failing hearts; however, no attempt has been made to diminish the antigenicity of ADAMPs and examine their impact in heart failure. In the heart, there are small histidyl dipeptides, such as carnosine, which can act as nucleophiles. Carnosine is synthesized by the enzyme carnosine synthase, which could bind with reactive aldehydes. Our preliminary studies show carnosine can bind with aldehyde modified protein adducts (like ADAMPs); its levels are depleted in failing hearts; and supplementing the precursor amino acid (β-alanine) improves cardiac function. Based on these preliminary results, we hypothesize that capping of ADAMPs with carnosine could limit inflammation and improve cardiac function in failing hearts. For this, we will examine the extent to which overexpression and deletion of CARNS affects cardiac function in failing hearts. Furthermore, we will examine how altering the levels of carnosine per se in the heart influences the capping of aldehyde modified protein adducts and subsequent immune responses. These studies create extensive opportunities for professional development and for the creation of new, fundamental insights into the pathophysiology of heart failure.