Novel role of ROCK2 in Immune Mechanisms of Takotsubo Cardiomyopathy - Takotsubo Cardiomyopathy (TCM) is an acute, life-threatening condition triggered by an intense physical or emotional stressor and characterized by cardiac dysfunction, apical ballooning of the left ventricle, and thinning of the ventricular wall. With maximal medical care, patients may recover, but they often live with permanent sequelae. Patients who have experienced an episode of TCM are at increased risk of an additional episode, increased risk of additional cardiovascular events, and reduced life expectancy. Importantly, there are no current formal recommendations for treatment or patient care post-TCM episode. Recent studies have demonstrated that TCM is associated with a robust immune response in both human patients and in preclinical rodent models, particularly an infiltration of macrophages into the cardiac tissue. In a similar manner, immune activation has been demonstrated to play a causal role in preclinical models of hypertension, or an elevation in blood pressure. Our laboratory has particular expertise in interrogating the immune contribution to hypertensive pathology and recently demonstrated a role for macrophages in hypertensive heart failure. My preliminary data confirm that mice treated with isoproterenol (ISO), a catecholamine that mimics the intense the stress response that occurs in the human condition, develop TCM with macrophage infiltration into the heart. Furthermore, I have found that the expression of the enzyme ROCK2 (Rho associate coiled-coil containing protein kinase 2), is elevated in left ventricle of these mice, concurrent with the observed increase in macrophages. Inhibition of ROCK2 using the novel pharmaceutical KD025 (Belumosudil) prevented the full development of TCM in mice. I have also found that KD025 treatment halts the progression of hypertension- induced cardiac fibrosis and in vitro, KD025 attenuates macrophage activation. Lastly, I have found that mice who have experienced an episode of TCM have a potentiated hypertensive response to low dose Angiotensin II (Ang II). These recent studies and my preliminary data lead me to the hypothesis that ROCK2 in macrophages promotes cardiac dysfunction in the acute phase of TCM and contributes to the elevated cardiovascular risk after a TCM episode. To test this hypothesis, I will use models of TCM and hypertension, cell culture, and transcriptomics to: Aim1 (K99): Determine the role of ROCK2 in isoproterenol-induced macrophage activation in TCM and Aim 2 (R00): Determine the mechanisms by which a history of TCM potentiates future hypertension through reprogramming of myeloid cells. During the K99 phase, I will receive training in RNA sequencing analysis, immune training assays, and assessing cardiac remodeling. Determining how ROCK2 contributes to TCM and whether ROCK2 contributes to increased cardiovascular risk post-TCM will greatly advance the field and result in new therapeutic opportunities. These proposed studies, along with my proposed career development plan, will provide a foundation for my career as an independent investigator in an outstanding environment.
