Calpain Inhibition Preserves Talin and Attenuates Right Heart Failure in Acute Pulmonary Hypertension

Abstract

Right heart failure from right ventricular (RV) pressure overload is a major cause of morbidity and mortality, but its mechanism is incompletely understood. We tested the hypothesis that right heart failure during 4 hours of RV pressure overload is associated with alterations of the focal adhesion protein talin, and that the inhibition of calpain attenuates RV dysfunction and preserves RV talin. Anesthetized open-chest pigs treated with the calpain inhibitor MDL-28170 (n ¼ 20) or inactive vehicle (n ¼ 23) underwent 4 hours of RV pressure overload by pulmonary artery constriction (initial RV systolic pressure, 64 6 1 and 66 6 1 mm Hg in MDL-28170 and vehicle-treated pigs, respectively). Progressive RV contractile dysfunction was attenuated by MDL-28170: after 4 hours of RV pressure overload, RV systolic pressure was 44 6 4 mm Hg versus 49 6 6 mm Hg (P ¼ 0.011), and RV stroke work was 72 6 5% of baseline versus 90 6 5% of baseline, (P ¼ 0.027), in vehicle-treated versus MDL-28170-treated pigs, respectively. MDL-28170 reduced the incidence of hemodynamic instability (death or systolic blood pressure of , 85 mm Hg) by 46% (P ¼ 0.013). RV pressure overload disrupted talin organization. MDL-28170 preserved talin abundance in the RV free wall (P ¼ 0.039), and talin abundance correlated with the maintenance of RV free wall stroke work (r ¼ 0.58, P ¼ 0.0039). a-actinin and vinculin showed similar changes according to immunohistology. Right heart failure from acute RV pressure overload is associated with reduced talin abundance and disrupted talin organization. Calpain inhibition preserves the abundance and organization of talin and RV function. Calpain inhibition may offer clinical utility in treating acute cor pulmonale.Keywords: right ventricular dysfunction; pulmonary hypertension; calpain; talin; heart failure Right ventricular (RV) failure from acute right ventricular pressure overload (RVPO) is a major cause of morbidity and mortality in conditions such as pulmonary embolism and hypoxic pulmonary vasoconstriction, and in the early period after cardiopulmonary bypass or cardiac transplantation (1, 2). In the past, the conventional understanding of the pathophysiology of acute RV failure attributed it either to RV ischemia or to abnormal loading conditions during RVPO. However, we and others (3-5) previously demonstrated that the pathophysiology is more complex: a brief period of RVPO without RV ischemia results in intrinsic RV contractile dysfunction that persists beyond the period of RVPO itself, despite the restoration of normal loading conditions. Thus, the mechanism of intrinsic contractile dysfunction provoked by RVPO remains uncertain.Current clinical treatments for acute RV failure from RVPO depend almost exclusively on inotropic therapy or measures intended to relieve the underlying RVPO, such as thrombolysis, pulmonary thromboendarterectomy, and pulmonary vasodilators. These measures often result in serious complications, do not fully mitigate the high mortality, and do not directly address the mechanisms o...

Calpain inhibition improves collateral-dependent perfusion in a hypercholesterolemic swine model of chronic myocardial ischemia

“…Calpain dependent regulation of talin has been well demonstrated in other studies 16 , and CI resulting in increased talin has been shown to improve microvascular contractility 17 . Another study utilizing a porcine model of right heart failure demonstrated that right ventricular (RV) pressure overload resulted in disrupted talin organization, while CI resulted in preservation in abundance and organization of talin, with an associated improvement in contractility 18 .…”

Noncanonical WNT Activation in Human Right Ventricular Heart Failure

“…Importantly, there is also evidence that calpain-μ contributes to pathologic RV remodeling. In an acute pressure overload-induced rabbit RVF model, direct right coronary artery infusion of the selective calpain inhibitor MDL-28710 partially rescued RV function and reduced cleavage of the cytoskeletal protein talin ( 55 ). Thus, our findings of ROR2 induction and activation of its downstream pathways, suggest a model ( Figure 5 ) whereby an embryonic WNT5a/ROR2 program is reactivated in the setting of RVF, which then promotes calpain-mediated cleavage of FLNA and likely other targets, ultimately leading to maladaptive cytoskeletal changes and worsening RVF.…”

Noncanonical WNT activation in human right ventricular heart failure

“…Importantly, there is also evidence that calpain contributes to pathologic RV remodeling. In an acute pressure overload-induced rabbit RVF model, direct right coronary artery infusion of the selective calpain inhibitor MDL-28710 partially rescued RV function and reduced cleavage of the cytoskeletal protein talin [46]. Thus, our findings of ROR2 induction and activation of its downstream pathways, suggest a model ( Figure 4 ) whereby an embryonic WNT5a/ROR2 program is reactivated in the setting of RVF, which then promotes calpain-mediated cleavage of FLNA and likely other targets, ultimately leading to maladaptive cytoskeletal changes and worsening RVF.…”