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ROLE OF THE LIM-DOMAIN PROTEINS LPP AND ZYXIN IN HYPERTENSION-INDUCED CARDIOVASCULAR REMODELING

Nahar, Taslima

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Abstract

Hypertension, a chronic and persistent increase in blood pressure, is a modifiable risk factor for, e.g. coronary heart disease, hemorrhagic stroke and end-stage renal failure. Despite the pathophysiological importance of hypertension, understanding of the cellular mechanisms at the onset of this disease remains elusive. During hypertension, vascular smooth muscle cells (VSMCs) are exposed to increased wall stress. This promotes a phenotype shift of the VSMCs to overcome the undue rise in wall stress and eventually reinstate vascular tone. At the cellular level, excessive stretch induces translocation of the mechanotransducer protein zyxin from focal adhesions to stress fibers and to some extent to the nucleus where it indirectly via myocardin-related transcription factor-A (MRTF-A) fine-tunes the expression of mechanosensitive genes. VSMCs isolated from 3-months old zyxin knockout (Zyxko) mice showed a synthetic phenotype. In contrast, only deoxycorticosterone acetate (DOCA)-salt treated very old (18-months) Zyxko mice revealed a prominent vascular phenotype exemplified by failure to develop hypertension, a lower resistivity index, i.e. peripheral resistance, and an altered composition of the extracellular matrix (ECM). The age dependency of the in vivo phenotype argues for a possible compensation by other LIM-domain proteins of the zyxin family. Therefore, the first aim was to analyze whether LPP (lipoma preferred partner) or TRIP6 (thyroid receptor interacting partner 6) might compensate for the loss of zyxin in hypertension-induced arterial remodeling. Like zyxin, LPP but not TRIP6 in vitro translocated from focal adhesions predominantly to actin stress fibers as well as to the nucleus upon exposure to supraphysiological stretch. Interestingly, only the level of LPP protein significantly declined in arteries of very old Zyxko mice. VSMCs isolated from 3-months old Lppko mice functionally mimicked the synthetic phenotype of VSMCs isolated from age-matched Zyxko mice. Although young Lppko mice (3 months old) failed to reveal a synthetic VSMC phenotype in experimental hypertension, their significantly lower resistivity index may point to the presence of some vascular dysfunction at this young age. Overexpression of either Lpp in Zyxko VSMCs or Zyx in Lppko VSMCs fully compensated for their alternate loss of function in restoring the contractile VSMC phenotype. Hence, these findings characterize zyxin as a novel regulator of the phenotypic shift of VSMCs during hypertension-induced arterial remodeling with LPP capable of reinforcing zyxin in preventing this shift to occur. Distinct from VSMCs, terminally differentiated cardiomyocytes (CMs) respond to arterial hypertension by increasing their cell size hence thickness of the ventricular wall (hypertrophy) thereby normalizing wall stress according to the law of Laplace. Following this compensatory CMs hypertrophy, loss of CMs as well as excessive deposition of ECM proteins by cardiac fibroblasts (CFBs) causes cardiac dysfunction. The mechanotransducer zyxin seems to be important for CMs survival. Therefore, the second aim of this work was to study the consequences of the loss of zyxin for cardiac function in DOCA-salt induced experimental hypertension. In fact, 12 months old Zyxko mice showed cardiac dysfunction possibly due to excessive cardiac fibrosis and the resulting stiffening of the heart. To corroborate this finding, a cardiac fibrosis model, where 3, 6 and 12 months old Zyxko and wild type (WT) mice are treated with a high dose of angiotensin II (Ang II) or saline delivered through implanted osmotic mini pumps, was established. In this model, untreated 3 months old Zyxko mice presented with a reduced diastolic but preserved systolic function as compared to age-matched WT mice. Upon Ang II treatment, systolic cardiac function progressively deteriorated in the Zyxko mice with age and this was paralleled by a prominent age-dependent rise in collagen deposition in the heart. The effects of Ang II on both interstitial and perivascular cardiac fibrosis were significantly less pronounced in age-matched WT mice, indicative of the development of a progressive restrictive cardiomyopathy in the Zyxko mice in this model. To identify key molecule(s) responsible for the profuse cardiac fibrosis in Zyxko mice, pro-fibrotic gene expression profiles were studied in adult cardiac fibroblasts (ACFs) isolated from Zyxko or WT mice that were exposed in vitro to transforming growth factor-β1. Prominent expression of connective tissue growth factor, collagens I and III as well as lysyl oxidase (LOX) by the Zyxko ACFs supports the notion that CFBs account for the excessive formation of scar tissue in the heart of these animals. Since LOX augments the formation of insoluble collagen deposits in the heart, namely by cross-linking them, it might be together with the enhanced synthesis of collagens I and III primarily responsible for the exaggerated cardiac fibrosis and hence cardiac dysfunction in the Zyxko mice. Whether the age-dependency of this cardiac phenotype is like the vascular phenotype related to a functional compensation between zyxin and LPP in the CFBs or even CMs remains to be determined. Nonetheless, it is likely that the lack of zyxin leads to an altered CM-ECM interaction facilitating CM apoptosis and in turn or in parallel excessive cardiac fibrosis hence contributing to the observed cardiac dysfunction in adult Zxyko mice. In summary, the findings of this study characterize the LIM-domain proteins zyxin and LPP as redundant protective molecules that help to maintain the contractile VSMC phenotype and thus contribute to impeding the development of hypertension-induced arterial and possibly cardiac remodeling. The temporal difference in the appearance of two distinct hypertension-induced phenotypes (vascular and cardiac) might be attributed to the differential abundance of zyxin and LPP in the respective tissue-resident cells contributing to the pathogenesis. Therefore, analysis of old Lppko as well as Lpp/Zyx double-knockout mice has the potential to shed more light on their possible functional compensation in the context of hypertension-induced cardiovascular remodeling processes.

Item Type: Dissertation
Supervisor: Hecker, Prof. Dr. Markus
Place of Publication: Heidelberg, Germany
Date of thesis defense: 19 October 2017
Date Deposited: 03 Nov 2017 12:25
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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