The loss of cardiac output immediately post-myocardial infarction (MI) triggers longer-term cardiac remodeling. MI remodeling consists of a loss of contractility and ventricular dilation leading to heart failure (HF). Strategies that maintin higher systolic function post-MI may circumvent the stimulus that ultimately leads to HF. One potential therapeutic target is Rad, a small GTPase that acts as a regulator of the L-type calcium channel; Rad loss promotes greater inward current, higher twitch calcium levels, greater fractional shortening of ventricular myocytes, and increased heart contractility. It is hypothesize that this improvement in calcium homeostasis and contraction can mitigate the loss of contractility post-MI. To test this hypothesis, Rad null mice will be subjected to coronary artery ligation, and serial echocardiography to monitor heart dimensions and function. Scar size will be evaluated using histology, and cytosolic calcium will be measured in stimulated isolated ventricular myocytes to determine if Rad null mice are protected from MI-induced calcium dysregulation, preventing loss of transient amplitude and the slowing of reuptake into the SR. In addition, the hypothesis that Rad null mice are protected from acute MI-induced necrosis and apoptosis will be tested using isolated perfused hearts subjected to ischemia, which will subsequently be stained and analyzed for infarct development. These results will also be investigated in vivo using late gadolinium enhanced MRI. It is hypothesized that deletion of Rad GTPase will prevent MI-induced heart failure through both preservation of cardiac output post-MI, and through the priming of the heart to reduce infarct development through cytoprotective pathways. These experiments will enable a better understanding of a potentially beneficial therapeutic protein that may both prevent acute cytotoxicity, as well as promote functional improvement after MI.
This proposal will test the hypothesis that Rad GTPase deletion will promote tissue survival and will promote myocardial function after ischemia, preserving cardiac output and obviating the hemodynamic trigger for cardiac remodeling that leads to pathological hypertrophic growth, remodeling, and heart failure. These findings will identify a novel method of cardioprotection that may be clinically relevant for post-myocardial infarction treatment of contractile dysfunction and the prevention of heart failure.
|Manning, Janet R; Chelvarajan, Lakshman; Levitan, Bryana M et al. (2018) Rad GTPase deletion attenuates post-ischemic cardiac dysfunction and remodeling. JACC Basic Transl Sci 3:83-96|
|Levitan, Bryana M; Manning, Janet R; Withers, Catherine N et al. (2016) Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart. J Cardiovasc Transl Res 9:432-444|
|Manning, Janet R; Withers, Catherine N; Levitan, Bryana et al. (2015) Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging. Am J Physiol Heart Circ Physiol 309:H1336-45|