The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. A broad array of potential therapeutic targets and regulators of age-associated modifications, specifically for vinculin, are presented. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts.
miR-448 in hearts of young dystrophic mice. The latter correlated with overexpression of the Ncf1 gene, encoding the NOX2 regulatory subunit p47phox. Specificity of Ncf1 targeting by miR-448 was confirmed by luciferase reporter assay. To study the effect of miR-448 silencing on molecular, cellular and functional properties of normal hearts, we intravenously injected wild type mice with LNA-NC and LNA-miR-448 inhibitors. qRT-PCR, western blotting, confocal imaging of ROS and intracellular Ca 2þ signals and echocardiography were employed. Acute inhibition of miR-448 resulted in an increase in Ncf1 expression as well as enhanced ROS production and augmented intracellular Ca 2þ signaling in isolated cardiomyocytes. In addition, prolong (over one month) inhibition of miR-448 led to the deterioration of cardiac functions and development of dilated cardiomyopathy and arrhythmia. Overall, WT mice with inhibited miR-448 mimicked many features of dystrophic cardiomyopathy. Our data suggest that downregulation of miR-448 relieves inhibition of translational initiation of Ncf1 in dystrophic cardiomyopathy. It results in an increase in Ncf1 expression and consequently in oxidative stress and enhanced Ca 2þ signaling in dystrophic heart well before cardiac dysfunction becomes evident.
Molecular and ultrastructural remodeling of the intercalated disc occurs with advanced age and onset of cardiomyopathy, yet the precise effect of this remodeling on mechanical function remains unclear. We employed recently-developed biophysical techniques to measure passive and active cardiac mechanics to investigate how intercalated disc remodeling affects structure and mechanical function with age. Nanoindentation of intact, living Drosophila heart reveals that juvenile myocytes are mechanically homogeneous; however, aging induces mechanical heterogeneity, indicated by increased transverse passive stiffness proximal to the intercalated disc (ID). Localized stiffening up to a 111% increase correlates with an 18% age-related decline in diastolic dimension (DD) as well as increased fascia adherens expression. On the other hand, aged specimens with stiffened IDs were found to have preserved systolic function, assessed by measuring shortening velocity under acute hemodynamic load, as compared to their juvenile counterparts. Aged specimens with no change in ID stiffness experienced reduced shortening velocities at all loads. Cardiac-specific vinculin overexpression stiffened IDs and increased shortening velocity and fractional shortening at all hemodynamic loads. Cardiac specific, RNAi-mediated knockdown of vinculin softened the IDs of intact hearts and reduced fractional shortening at all loads. These data indicate that increased expression of vinculin at the ID results in a stiffer cortical cytoskeleton which acts as a more stable anchor against which the myocytes can shorten. These findings have potential implications for geriatric patients with diastolic heart failure, in whom increased vinculin expression at the intercalated disc, concomitant with increased diastolic stiffness but preserved ejection fraction, has been observed.
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