The Muscle Ankyrin Repeat Proteins CARP, Ankrd2, and DARP Are Not Essential for Normal Cardiac Development and Function at Basal Conditions and in Response to Pressure Overload

Abstract

Ankrd1/CARP, Ankrd2/Arpp, and Ankrd23/DARP belong to a family of stress inducible ankyrin repeat proteins expressed in striated muscle (MARPs). The MARPs are homologous in structure and localized in the nucleus where they negatively regulate gene expression as well as in the sarcomeric I-band, where they are thought to be involved in mechanosensing. Together with their strong induction during cardiac disease and the identification of causative Ankrd1 gene mutations in cardiomyopathy patients, this suggests their important roles in cardiac development, function, and disease. To determine the functional role of MARPs in vivo, we studied knockout (KO) mice of each of the three family members. Single KO mice were viable and had no apparent cardiac phenotype. We therefore hypothesized that the three highly homologous MARP proteins may have redundant functions in the heart and studied double and triple MARP KO mice. Unexpectedly, MARP triple KO mice were viable and had normal cardiac function both at basal levels and in response to mechanical pressure overload induced by transverse aortic constriction as assessed by echocardiography and hemodynamic studies. Thus, CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to mechanical pressure overload.

Global Deletion of Ankrd1 Results in a Wound-Healing Phenotype Associated with Dermal Fibroblast Dysfunction

“…Previous reports of deletion of one or all of the MARPs have detected minor effects. 6,7,19 The present findings in ischemic flaps and excisional wounds are highly consistent with the concept that ANKRD1 abundance becomes a rate-limiting factor when cells and tissues are challenged by injury and stress.…”

“…16 Deletion of all three MARPs provides evidence of skeletal muscle weakness, 6 but the mouse strains in that study showed no developmental abnormalities, as in this report, or, in a more recent report, response to cardiac pressure overload. 7 …”

Disturbance in Z-Disk Mechanosensitive Proteins Induced by a Persistent Mutant Myopalladin Causes Familial Restrictive Cardiomyopathy

“…Ablation of all forms of muscle ankyrin repeat proteins (MARPs), including CARP, enhances the MyoD and MLP expression in skeletal muscle (23). While ablation of CARP or MARPs has been shown to not affect the cardiac function similar to our Mypn Q526X homozygotes (24), cardiac-restricted CARP over-expression results in an inhibition of hypertrophic and fibrotic remodeling via reduced TGF-β and ERK1/2 (18). Our previous Mypn Y20C transgenic mouse model ( Central Illustration ) suggested a crucial role of nuclear WT-Mypn by demonstrating the development of hypertrophic cardiomyopathy in vivo as a result of perturbed nuclear shuttling of Mypn (9).…”

Multifunctional protein: cardiac ankyrin repeat protein

“…They discovered that CARP Tg mice developed less hypertrophy than wild-type mice in cardiac hypertrophy models, including transverse aortic constriction (TAC) and isoproterenol, and concluded that CARP could attenuate cardiac hypertrophy mediated by inhibition of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and transforming growth factor β (TGF-β) pathways and then decrease fibrosis deposition in the heart. Conversely, Bang et al (2014) found that CARP is not essential for normal cardiac development and functions in basal conditions and in response to mechanical pressure overload; Chen et al (2014) demonstrated that CARP promoted cardiomyocyte hypertrophy through calcineurin accumulation.…”