Cardiovascular disease is the number one cause of death in the US (e.g., heart failure); with aging and hypertrophy the two foremost risk factors. Aging increases the cardiac afterload and decreases contractile reserve that eventually compromise heart function. This sets up a vicious cycle (contractile defects?remodeling?compromised heart function) that spirals the heart toward failure culminating in death. Inotropic strategies to increase contractility have been developed to aid the heart. This inotropic support will break this vicious cycle to avert the development of heart failure to preserve life and the quality of life (healthspan). Unfortunately, current inotropic strategies are confounded by increasing cytosolic Ca2+, compromising relaxation, and/or causing arrhythmias which accelerates the spiral into heart failure and hastens death. We have a novel approach to increase inotropy without the deleterious effects of existing inotropes. Using the strengths of smartly formulating proteins, we have shown that cardiac contractility and contractile reserve can be directly controlled and strongly influenced by manipulating the Ca2+ dependent switch in cardiac muscle, troponin C (TnC). Our pioneering construct, L48Q TnC, is a strong Ca2+ sensitizer with properties of an ideal positive inotrope. Our preliminary results clearly demonstrate that the in vivo expression of L48Q TnC increases cardiac contractility and contractile reserve without any deleterious effects associated with other inotropic strategies. The objective of this proposal is to determine the cardiac effects of L48Q TnC in the senescent or hypertrophic mouse. We hypothesize that L48Q TnC will increase contractile reserve to improve heart function and aid cardiac performance during aging or hypertrophy. Excitingly, our preliminary data support our hypothesis in that L48Q TnC transduced mice (via Adeno Associated Virus serotype 9 - AAV9) maintain better cardiac performance upon aging or in hypertrophic mice. We will test our central hypothesis by pursuing the following aims:
Aim 1 - assess if L48Q TnC can improve cardiac performance of aging mice;
Aim 2 - assess if L48Q TnC can maintain cardiac performance in hypertrophy. Our notable preliminary findings demonstrate that the compromised cardiac performance of hypertrophy and senescent mice can be prevented by L48Q TnC. These data strongly support that L48Q TnC is an ideal positive inotrope (i.e., no deleterious effects) that can aid the heart in breaking the vicious cycle that spirals into heart failure and death. These studies will provide a new direction (i.e., inotropic support via L48Q TnC) that can be used therapeutically to enhance heart function in a variety of cardiomyopathies associated with aging
Aging and hypertrophy are major risk factors for the development of cardiovascular disease. The relevance of this proposal to public health is by developing a novel treatment strategy to help the heart perform better to overcome these risk factors.
| Siddiqui, Jalal K; Tikunova, Svetlana B; Walton, Shane D et al. (2016) Myofilament Calcium Sensitivity: Consequences of the Effective Concentration of Troponin I. Front Physiol 7:632 |
