Cardiovascular disease (CVD) is the leading cause of death and disability in industrialized nations and its prevalence is rising rapidly in developing nations. In particular, heart failure (HF) has been singled out as an epidemic and is a staggering clinical and public health problem associated with significant morbidity, mortality, and healthcare expenditures. Current therapies only delay morbidity and mortality in patients with chronic systolic heart failure, as disease progression typically continues unabated resulting in death. Novel therapies for heart failure are desperately needed, which will require a greater understanding of the underlying molecular mechanisms that underlie this disease. A universal characteristic of the failing heart is impaired Ca2+ cycling through the sarcoplasmic reticulum (SR), the major internal store of Ca2+ in cardiomyocytes. Indeed, cardiomyocytes from failing hearts consistently show defective excitation contraction-coupling characterized by diminished SR Ca2+ sequestration and decreased intracellular Ca2+ transients, events that contribute to impaired contractility and relaxation that culminate in depressed pumping action of the heart. Ca2+ re- sequestration into the SR is mediated by a Ca2+-ATPase (SERCA), whose activity is known to be reversibly regulated by the small integral membrane proteins phospholamban (PLN) and sarcolipin (SLN). Enhancing SERCA activity and function has been suggested as an important clinical approach for treating HF by loading the SR with greater Ca2+ levels to augment Ca2+ release resulting in greater myocyte contractility during systole. Apart from gene therapy to actually replace SERCA protein (which is currently in human clinical trails with an AAV vector), we currently lack a facile therapeutic approach aimed at correcting alterations in Ca2+ and SERCA function in the heart. However, modulation of SERCA activity through manipulation of PLN or small peptides like it represents a novel and straightforward therapeutic approach. Our lab has identified a novel micropeptide encoded by a muscle-specific RNA currently annotated as a long non-coding RNA (lncRNA), which we have named DWORF (DWarf Open Reading Frame). DWORF shares strong sequence homology and predicted domain structure with the well-described SERCA inhibitors PLN and SLN and our preliminary results show it localizes to the SR and can bind directly to SERCA. We hypothesize that DWORF is functionally homologous to PLN and SLN and that it regulates SERCA activity and myocyte contractility. We will utilize biochemical, cell-based, and genetic approaches, along with in vivo physiological studies to define the function and regulation of DWORF in the heart and to examine how it might impact cardiac disease susceptibility. Collectively, our studies will provide new insights into Ca2+ cycling and regulation in the heart and potentially provide the basis for development of a novel therapeutic target in cardiovascular disease.

Public Health Relevance

Proper calcium cycling and signaling is essential for the contractile performance of the heart and defects in calcium homeostasis are a major underlying factor in cardiovascular disease. The goals of this project are to define the function and regulation of a novel cardiac micropeptide that appears to control myocyte contractility through a mechanism involving calcium cycling. We will examine how the expression and function of this novel micropeptide change during heart disease. Manipulation of the activity of this micropeptide could serve as a potential strategy to enhance cardiac contractility in the setting of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL129674-03
Application #
9441042
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Wayne C
Project Start
2016-02-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Baskin, Kedryn K; Makarewich, Catherine A; DeLeon, Susan M et al. (2017) MED12 regulates a transcriptional network of calcium-handling genes in the heart. JCI Insight 2:
Anderson, Douglas M; Makarewich, Catherine A; Anderson, Kelly M et al. (2016) Widespread control of calcium signaling by a family of SERCA-inhibiting micropeptides. Sci Signal 9:ra119