Microdomains of GC1 Cardioprotective Signaling
We previously discovered that the nitric oxide receptor soluble guanylyl cyclase (GC1) is dysregulated in the hypertrophied, dysfunctional left ventricle. Both pressure- and volume-overload induce re-localization of GC1 away from caveolae, invaginations of the plasmalemma that compartmentalize signal transduction. Within caveolae, GC1 appears protected from oxidation and remains responsive to nitric oxide (NO). In the hypertrophied, failing heart, GC1 that is outside of caveolae becomes oxidized and NO-responsiveness is blunted. We subsequently found that β-blocker therapy, a cornerstone of guideline directed medical therapy (GDMT) of heart failure, alters GC1 signaling in the diseased heart in a way that establishes potentially novel, but latent, cardioprotective cascades. In the face of volume overload stress, β-blockade prevented myocardial GC1 dissociation from caveolae, restored NO-responsiveness of GC1 outside of caveolae, and induced functional coupling between β3 adrenoceptor (β3AR) and GC1 within a non-lipid raft membrane microdomain. Intriguingly, this functional β3AR/GC1 coupling was specific to the non-lipid raft microdomain and was not found in either control nor untreated, hypertrophied hearts.
We hypothesize that GDMT changes the NO- responsiveness and functional coupling of GC1 within distinct membrane microdomains of cardiac myocytes, thereby resulting in untapped cardioprotective potential that differs from that in non-failing or untreated failing hearts. In this project, we aim to: 1) determine the physiological function of plasmalemmal caveolae- vs. dyadic junction-associated GC1/cGMP signaling in cardiac myocytes; 2) define the effect of GDMT on myocardial caveolae- vs. dyadic junction associated GC1/cGMP signaling in the pressure overloaded heart; and 3) elucidate how GDMT promotes sGC caveolae-localization and enhances NO-responsiveness.
Active Funding: R01 HL138528 (PI: Tsai)
Completed Funding: K08 HL109159 (PI: Tsai)
Molecular Pathophysiology Right Ventricular Dysfunction (RVD) and Right Heart Failure (RHF)
Right ventricular dysfunction (RVD) independently confers increased morbidity and mortality amongst heart failure patients, irrespective of their left ventricular function. Despite the high prevalence and clinical significance of RVD, our understanding of the molecular pathophysiology of RVD is limited and none of the evidence-based medications for heart failure address RVD. Using both animal models of right heart failure and myocardial tissue from advanced heart failure patients, we have identified genetic drivers and repressors of RVD. Current projects aim to elucidate the mechanisms by which these select pathways regulate RV function.
Active Funding: R03 HL133706 (PI: Tsai)