Cofilin-2 Phosphorylation and Sequestration in Myocardial Aggregates

Abstract

BACKGROUND Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM). This suggests a potential underlying cause for the one-third of cases, traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. OBJECTIVE We sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer’s disease. METHODS Aggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence) and the findings validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro using pharmacological and genetic gain and loss of function approaches. RESULTS Aggregates in the human myocardium were enriched for cofilin-2, an actin-depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease’s morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of “stress-like” fibers and severely impaired cardiomyocyte contractility. CONCLUSIONS Our study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism between certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies.

Aβ Amyloid Pathology Affects the Hearts of Patients With Alzheimer’s Disease

“…Here, we tested whether other mechanisms link cardiac dysfunction to the brain disorder in the absence of any known causes of compromised cardiovascular function. This possibility was suggested by our recent discoveries of: 1) protein aggregates in iDCM (9); 2) common genetic mutations in AD and iDCM (9); and 3) common components of the AD and iDCM aggregates (10). Thus, low perfusion and amyloid angiopathy may not be the sole contributors to the heart-to-brain connection, and the possibility that patients with AD would present with myocardial dysfunction was a reasonable hypothesis.…”

“…Additionally, a number of more recent discoveries suggest a closer common pathogenesis between the 2 conditions. These include the discovery that protein aggregates deposit in the myocardium of patients affected by idiopathic dilated cardiomyopathy (iDCM) (9), and that such deposits are biochemically akin to those found in AD (10). Moreover, genetic variants in the same gene associated with early-onset AD (presenilin = PSEN ) were reported in familial (11) and sporadic cases (9) of iDCM.…”

Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

“…An "heart-brain continuum" hypothesis has been made based on the fact that AD and some cardiac pathologies share many features, including common risk factors, similar protein aggregates and genetic mutations [87]. Indeed, protein aggregates found in the myocardium of idiopathic DCM patients are biochemically similar to brain AD deposits, and soluble pre-amyloid oligomers are commonly found in heart failure patients [89]. Importantly, abnormal protein oligomers/aggregates have been reported to disturb Ca 2+ homeostasis and contribute to the cardiac pathology [90].…”

Calcineurin signaling in the heart: The importance of time and place

“…Calcineurin activates Slingshot making cofilin-mediated damage an indirect target of calcineurin [217, 218]. Hyperphosphorylated cytoplasmic cofilin aggregates have been found in the hearts of patients with idiopathic cardiomyopathy [219]. Therefore, whether calcineurin's impact on cofilin is protective or pathological may depend on context.…”