Heart failure affects 2-4 million individuals in America and over 15 million people worldwide. Hypertension is the greatest risk factor with over two-thirds of heart failure patients having a history of high blood pressure. Cardiac remodeling in hypertension or pressure overload is defined by concentric cardiac hypertrophy followed by dilatation with systolic failure. Many individual signaling elements and pathways that can regulate cardiovascular remodeling have been identified, however there is a great need to integrate this data and to discover novel mechanisms which will lead to the development of new therapeutic targets and approaches to heart failure. A commonality of the findings to date is the importance of kinases and regulation of proteins by phosphorylations in cardiac hypertrophy and function. The development of proteomics technology has made it possible to simultaneously analyze the abundance of several hundred phosphoproteins in a tissue or cell without apriori knowledge of function or distribution. Advances in analytic approaches use changes in phosphoprotein expression patterns to discover new phosphorylation signaling pathways and networks. This proposal focuses solely on serine and threonine phosphorylations in hypertensive heart failure since several serine-threonine kinases, including MAPKs, are implicated in myocyte hypertrophy, fibrosis, and apoptosis. We will apply phosphoprotein profiling to three defined cardiac phenotypes;1) normal;2) compensated hypertrophic;and 3) dilated/failing from three different rodent models of hypertensive and pressure-overload, i.e., Dahl salt-sensitive (S), spontaneously hypertensive - heart failure prone (SHHF), and aortic banded Wistar rats.
Aim 1 is to identify novel patterns of serine-threonine phosphorylated proteins that cluster with cardiac hypertrophy. After measuring cardiac size/function, we will identify phosphoprotein expression patterns that are uniquely common to hypertrophic hearts from Dahl S, SHHF rats, and aortic banded Wistar rats, and specifically not observed in normal hearts from their control counterparts: Dahl R and Wistar rats. These are candidate phosphoproteins for cardiac hypertrophy.
Aim 2 is to identify novel patterns of serine-threonine phosphorylated proteins that cluster with cardiac dilatation/failure. We will identify phosphoprotein expression patterns that are uniquely common to dilated hearts from Dahl S. SHHF, and aortic-banded Wistar rats and specifically not in both normal and hypertrophic hearts from their counterparts. These will be the best candidate phosphoproteins for cardiac dilation/failure. The identification of major patterns of phosphoproteins in the heart associated with hypertrophy and dilatation/failure will provide critical and new signaling insights into pathogenesis and function in hypertensive cardiac remodeling. The results will lead to testable hypotheses for specific signaling pathways in heart failure and the development of phosphorylation signaling pathways or networks. This will move us toward our overall goal of determining new therapeutic approaches and novel targets for heart failure.

Public Health Relevance

Heart failure affects 2-4 million individuals in America and over 15 million people world- wide. The overall goal of this project is to discover underlying signaling pathways and molecular mechanisms important in its pathogenesis and cardiac remodeling with the overall goal of developing new therapeutic strategies and targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL096031-02
Application #
8020918
Study Section
Special Emphasis Panel (ZRG1-CVRS-K (02))
Program Officer
Adhikari, Bishow B
Project Start
2010-02-04
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2011
Total Cost
$198,733
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Kotlo, K; Samarel, A M; Chen, H Y et al. (2016) Global comparison of phosphoproteins in human and rodent hearts: implications for translational studies of myosin light chain and troponin phosphorylations. Springerplus 5:808
Kotlo, Kumar; Xing, Yongna; Lather, Sonia et al. (2014) PR65A phosphorylation regulates PP2A complex signaling. PLoS One 9:e85000
Kotlo, Kumar; Bhattacharyya, Sumit; Yang, Bo et al. (2013) Impact of salt exposure on N-acetylgalactosamine-4-sulfatase (arylsulfatase B) activity, glycosaminoglycans, kininogen, and bradykinin. Glycoconj J 30:667-76
Hesabi, Bahar; Danziger, Robert S; Kotlo, Kumar U (2012) Heterogeneous nuclear ribonucleoprotein A1 is a novel cellular target of atrial natriuretic peptide signaling in renal epithelial cells. Cell Signal 24:1100-8
Grillon, Jean Michel; Johnson, Keven R; Kotlo, Kumar et al. (2012) Non-histone lysine acetylated proteins in heart failure. Biochim Biophys Acta 1822:607-14
Kotlo, Kumar; Johnson, Keven R; Grillon, Jean M et al. (2012) Phosphoprotein abundance changes in hypertensive cardiac remodeling. J Proteomics 77:1-13
Kotlo, Kumar U; Hesabi, Bahar; Danziger, Robert S (2011) Implication of microRNAs in atrial natriuretic peptide and nitric oxide signaling in vascular smooth muscle cells. Am J Physiol Cell Physiol 301:C929-37