Deficiency of Actinin-Associated LIM Protein Alters Regional Right Ventricular Function and Hypertrophic Remodeling

Abstract

Targeted deletion of actinin-associated LIM protein (ALP) in mice leads to right ventricular (RV) dysplasia and a mild RV cardiomyopathy. Although the phenotype has been thoroughly characterized, the mechanisms leading from the cytoskeletal defect to the disease are unclear. We hypothesized that ALP deficiency may be associated with (1) changes in regional systolic dysfunction and (2) regional dysregulation of hypertrophic growth, in accordance with the restricted expression of ALP in the outflow tract of the RV. We examined RV regional epicardial systolic strains with respect to end-diastole in ALP knockout (ALPKO) mice and wild-type controls using an open-chest preparation. Strain components were consistently lower in the ALPKO mice than wild-type controls (second principal strain E 2 : p = 0.05). RV pressure was slightly but not significantly lower in ALPKO mice as well. To assess regional growth, geometric remodeling was analyzed in ALPKO and wild-type mice after 4 weeks of chronic hypoxia (11% oxygen). The average amount of RV wall thickening in response to hypoxia was reduced to 11% in the ALPKO mice compared with 44% in the wild-type controls. In summary, the results are consistent with the view that disruption of ALP is associated with diminished RV contractile function as well as altered hypertrophic remodeling.

siRNA knock down of casein kinase 2 increases force and cross-bridge cycling rates in vascular smooth muscle

“…Actinin-associated LIM protein has been shown to be upregulated during differentiation of smooth muscle into a contractile phenotype (40). Deficits in actininassociated LIM protein in cardiac muscle have been shown to result in diminished ventricular contractility (29,39). ␣-Actinin has recently been shown to be directly involved in and necessary for the development of active force, at least in airway smooth muscle (56).…”

Optimizing cardiac material parameters with a genetic algorithm

“…This scheme can be applied to experimental measurements where strains are computed from epicardial surface marker or ultrasonic crystal displacements (Emery et al, 1997;Omens et al, 1993). Recently, Lorenzen-Schmidt et al (2005) measured epicardial strains concurrently on the right ventricular wall and outflow tract of the heart; such data would allow for two-point optimizations like our Scenario B.…”

Novel polymorphisms in PDLIM3 and PDLIM5 gene encoding Z‐line proteins increase risk of idiopathic dilated cardiomyopathy

“…Functionally, these proteins participate in the formation of sarcomeric complexes at the Z ‐line and interact with various proteins through their LIM domains, particularly with signalling factors . ALP and ENH are essential for proper heart development and contractility in hearts, as a PDLIM3 or PDLIM5 deficiency in mice results in DCM . The important roles of ALP and ENH in heart function make them two promising, candidate genes for cardiomyopathy.…”

“…A potentially pathogenic frameshift mutation (M60Tfs1X) of PDLIM3 was reported in a patient with DCM . Meanwhile, in mice, ablation of PDLIM3 results in primarily right ventricular dysmorphogenesis, a decrease in trabeculation and mild DCM . Moreover, Elisabeth and coworkers found that tight regulation of ALP is essential for a proper balance between maintenance of the extracellular matrix and the formation of fibrotic scars .…”