This application proposes to explore a novel signaling pathway regulating the process of pathologic cardiac remodeling. Cardiac remodeling represents the pathologic alterations in ventricular structure and function which contribute to heart failure and death. Our laboratory has explored downstream anti-remodeling signaling regulated by the signaling molecule protein kinase G I? (PKGI?). Our prior published studies have revealed a direct role of PKGI? in inhibiting pathologic cardiac remodeling in vivo. PKGI activating therapies are under investigation in humans with heart failure, but have been limited primarily by excess hypotension arising from PKGI induced vasodilation. In preliminary studies we have therefore explored downstream PKGI? substrates in the myocardium in order to identify signaling mechanism which may specifically inhibit remodeling but avoid excess vasodilation. Our preliminary data reveal mixed linage kinase 3 (MLK3) as a PKGI? anti-remodeling substrate. They also identify increased LV pressure overload-induced cardiac remodeling in MLK3 knockout mice, as well as systemic hypertension in these mice. Based on these and other preliminary data we propose to test the hypothesis that MLK3 mediates PKGI? anti-remodeling effects through kinase-dependent effects in the CM, and kinase-independent effects on vascular tone. We propose to test this hypothesis through 3 specific aims: SA1) To determine the role of MLK3 in mediating the anti-remodeling effects of PKGI? signaling; SA2) To determine the kinase-dependent mechanisms through which MLK3 inhibits cardiac remodeling; SA3) To determine the kinase-independent mechanisms through which MLK3 reduces blood pressure. These proposed studies utilize in vitro approaches as well as multiple innovative mouse models. Successful completion of these studies has the potential to identify MLK3 kinase activation as a novel therapeutic strategy for cardiac remodeling. Further, these studies will provide experimental evidence to address the novel paradigm that PKGI? inhibits cardiac remodeling and reduces blood pressure through independent signaling mechanisms.

Public Health Relevance

Heart failure, a major cause of death in the US, occurs when heart muscle becomes too weak and too stiff to circulate blood effectively. This progressive weakening and stiffening is called cardiac remodeling. We recently found that a molecule called PKG, which resides in the heart and other cardiovascular tissues, protects against cardiac remodeling. Unfortunately drugs that target PKG have not provided the expected benefits to heart failure patients. In the current proposal we have begun to investigate how PKG prevents remodeling, so that we might find new ways to harness the PKG effect in humans. We will focus on understanding one PKG cooperating molecule we have identified called MLK3, by investigating how MLK3 functions in the heart and the blood vessel to prevent remodeling. The findings from these studies can identify MLK3 as a potential new drug target and could offer novel strategies to target the PKG protective effect in humans with heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL131831-03
Application #
9462211
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
OH, Youngsuk
Project Start
2016-05-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
Salvador, Ane M; Moss, M Elizabeth; Aronovitz, Mark et al. (2017) Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation. Physiol Rep 5:
Nevers, Tania; Salvador, Ane M; Velazquez, Francisco et al. (2017) Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure. J Exp Med 214:3311-3329
Morine, Kevin J; Qiao, Xiaoying; Paruchuri, Vikram et al. (2017) Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling. Heart Vessels 32:628-636