Cytoskeletal role in protection of the failing heart by β-adrenergic blockade

Abstract

Formation of a dense microtubule network that impedes cardiac contraction and intracellular transport occurs in severe pressure overload hypertrophy. This process is highly dynamic, since microtubule depolymerization causes striking improvement in contractile function. A molecular etiology for this cytoskeletal alteration has been defined in terms of type 1 and type 2A phosphatase-dependent site-specific dephosphorylation of the predominant myocardial microtubule-associated protein (MAP)4, which then decorates and stabilizes microtubules. This persistent phosphatase activation is dependent upon ongoing upstream activity of p21-activated kinase-1, or Pak1. Because cardiac ␤-adrenergic activity is markedly and continuously increased in decompensated hypertrophy, and because ␤-adrenergic activation of cardiac Pak1 and phosphatases has been demonstrated, we asked here whether the highly maladaptive cardiac microtubule phenotype seen in pathological hypertrophy is based on ␤-adrenergic overdrive and thus could be reversed by ␤-adrenergic blockade. The data in this study, which were designed to answer this question, show that such is the case; that is, ␤ 1-(but not ␤ 2-) adrenergic input activates this pathway, which consists of Pak1 activation, increased phosphatase activity, MAP4 dephosphorylation, and thus the stabilization of a dense microtubule network. These data were gathered in a feline model of severe right ventricular (RV) pressure overload hypertrophy in response to tight pulmonary artery banding (PAB) in which a stable, twofold increase in RV mass is reached by 2 wk after pressure overloading. After 2 wk of hypertrophy induction, these PAB cats during the following 2 wk either had no further treatment or had ␤-adrenergic blockade. The pathological microtubule phenotype and the severe RV cellular contractile dysfunction otherwise seen in this model of RV hypertrophy (PAB No Treatment) was reversed in the treated (PAB ␤-Blockade) cats. Thus these data provide both a specific etiology and a specific remedy for the abnormal microtubule network found in some forms of pathological cardiac hypertrophy. microtubule; hypertrophy; heart failure IN 1993 A UNIQUE CYTOSKELETAL alteration was reported in the hypertrophying heart (51, 52). It was discovered that in myocardium hypertrophying in response to pathological pressure overloading, but not in response to an equivalent degree and duration of physiological volume overloading, there is a persistent increase in microtubule network density that causes contractile dysfunction. This cytoskeletal alteration becomes more pronounced during the deterioration of initially compensatory right ventricular (RV) or left ventricular (LV) pressure overload hypertrophy into the congestive heart failure state, both in animal models of human disease (47, 48) and in human disease itself (58). In addition to contributing to the systolic and diastolic contractile dysfunction that is characteristic of pathological hypertrophy (11), the extensive decoration of cardiomyocyte microtubules wi...

miR‐30c Mediates Upregulation of Cdc42 and Pak1 in Diabetic Cardiomyopathy

“…This was further supported by the findings that overexpression of miR‐30c resulted in a decreased expression of hypertrophic marker ANP and a decrease in cardiomyocyte size in HG‐treated cells, indicating attenuation of HG‐induced cardiomyocyte hypertrophy. Increased cardiac expression of Cdc42 and Pak1 has been reported in different animal models of cardiac hypertrophy, suggesting their prohypertrophic role. In contrary, two studies have reported Cdc42 and Pak1 to be antihypertrophic; Maillet et al.…”

Mechanical Stretch-Induced Activation of ROS/RNS Signaling in Striated Muscle

“…In diseases of both the heart (i.e., cardiomyopathy, arrythmia) and skeletal muscle (i.e., muscular dystrophy), pre-clinical studies targeting either the MT cytoskeketon (i.e., MT network destabilization) (11,32,38,39) or Nox-dependent ROS production (i.e., non-specific Nox inhibition) (38,83,84) have shown benefit and, thus, provide proof of concept for these approaches. The use of new techniques, reagents, and models will undoubtedly reveal new mechanistic details on the mechanoactivation of ROS/RNS production and oxidative/nitrosative signaling that will translate to new more specific targets for therapeutic intervention.…”

Novel roles of PAK1 in the heart

“…Excellent evidence to support this comes from the observation that constitutively active PAK1 and ligands stimulating these receptors produce the same cytoskeletal re-organization in mammalian cells 12 , 13 , 15 . Interestingly, recent studies have indicated that PAK1 is activated by a variety of growth factors such as EGF and other extracellular factors such as angiotensin II 16 and isoproterenol (ISO) 6 , 17 . These observations reflect the complexity of PAK1 upstream signaling pathways that are still not well understood.…”