Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure

Satoh, Shuichi; Ueda, Yuichi; Koyanagi, Masamichi; Kadokami, Toshiaki; Shinoda, Masahiro; Yoshikawa, Yutaka; Makino, Naoki

doi:10.1016/s0022-2828(02)00278-x

Cited by 97 publications

(71 citation statements)

References 35 publications

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“…PM 2.5 exposure increased cardiac RhoA activation, with reversal of these effects by fasudil, strongly indicating that RhoA/ROCK plays a significant role in mediating the effects of inhaled particulates on cardiac remodeling and BP. RhoA/ROCK has been demonstrated to be rapidly activated in response to various stimuli (3,18,23,44). Overexpression of constitutively active RhoA or dominant negative mutants in cardiomyocytes modulates the expression of various genes and pathways involved in cardiac hypertrophy (3,10,24), whereas ROCK inhibition attenuates cardiac hypertrophy in hypertensive strains and in response to exogenous ANG II (44,54).…”

Section: Discussionmentioning

confidence: 99%

“…RhoA/ROCK has been demonstrated to be rapidly activated in response to various stimuli (3,18,23,44). Overexpression of constitutively active RhoA or dominant negative mutants in cardiomyocytes modulates the expression of various genes and pathways involved in cardiac hypertrophy (3,10,24), whereas ROCK inhibition attenuates cardiac hypertrophy in hypertensive strains and in response to exogenous ANG II (44,54). Recent studies (18,23,44,54) have also suggested an important role for RhoA/ROCK in myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of constitutively active RhoA or dominant negative mutants in cardiomyocytes modulates the expression of various genes and pathways involved in cardiac hypertrophy (3,10,24), whereas ROCK inhibition attenuates cardiac hypertrophy in hypertensive strains and in response to exogenous ANG II (44,54). Recent studies (18,23,44,54) have also suggested an important role for RhoA/ROCK in myocardial fibrosis. A characteristic consequence of inhibition of ROCK is an amelioration of left ventricular fibrosis, as has been previously demonstrated in these studies.…”

Section: Discussionmentioning

confidence: 99%

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Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Zhao¹,

Yue²,

Xu³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

110

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Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of Ͻ2.5 m (PM2.5) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM2.5 or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM 2.5 exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM 2.5 exposure along with increased expression of the guanine exchange factors (GEFs) PDZRhoGEF and p115 RhoGEF in PM 2.5-exposed mice. Parallel with increased RhoA activation, PM 2.5 exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM2.5 potentiates cardiac remodeling in response to ANG II through RhoA/ Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution. hypertension; vasoconstrictors; angiotensin II AMBIENT AIR POLLUTION mediated by fine particulate matter (PM) of Ͻ2.5 m in aerodynamic diameter (PM 2.5 ) has been associated with adverse cardiovascular outcomes (8,31,39,49). One important mechanism is the elevation in blood pressure (BP) that may occur within hours to days after exposure to high concentrations of PM 2.5 (6,16,21,52). Recent studies (21, 58) have shown that commonly encountered levels of airborne pollutants can result in a prohypertensive response in humans that may be exaggerated in predisposed individuals. This potentiating effect of inhaled particulates has been noted with other chronic conditions or risk factors such as atherosclerosis, diabetes, and postmenopausal status (31,40,49). Although the precise mechanisms remain elusive, there is increasing evidence that PM 2.5 exposure results in rapid changes in the vasculature (7, 32). We (51) have previously shown that PM 2.5 exposure results in the activation of RhoA/Rho-kinase (ROCK) through ROS pathways and hypothesized that this important signaling cascade may mediate at least some of the prohypertensive effects of PM 2.5 . Given the important role of RhoA/ ROCK in a multitude of processes, including the regulation of smooth muscle tone, cellular migration, and hypertrophy (36,47), in the present study we examined the effect of PM 2.5 exposure on vascular function and cardiac remodeling and tested the effects of ROCK antagonism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Zhao¹,

Yue²,

Xu³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

110

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“…43 As mentioned earlier, the small G proteins, such as Ras, Rho and Rab, are the likely downstream targets after activation of these receptors, and there is considerable interest in these proteins both as mediators of myocyte hypertrophy and as therapeutic targets. [44][45][46] Against this background, it is interesting that a significant proportion of the cluster of signal transduction-related genes showing increased expression in late LVH belong to the small GTPase family and included the ras homolog gene family, member Q (also known as TC10 or Rhoq), Rho-associated coiled-coil forming kinase 2 (ROCK2) and RAS-related protein 1a (Figure 3a). It has been shown that the Cbl/ CAP/TC10 insulin signaling pathway is active in cardiac muscle and is impaired during obesity and insulin deficiency, 47 but to our knowledge, this is the first time that TC10 is related to both hypertension and heart hypertrophy.…”

Section: Signal Transductionmentioning

confidence: 99%

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

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Left ventricular hypertrophy (LVH), a common consequence of systemic hypertension associated with poor clinical outcome, is also a potentially reversible condition. Here, we probed the molecular pathways that underpin the development of LVH and their modulation by antihypertensive regimens that reversed LVH. Spontaneously hypertensive rats were studied at 12 (early LVH) and 48 weeks (late LVH), respectively, with normotensive Wistar-Kyoto rats as age-matched controls. Three treatment groups were maintained for 36 weeks on the following regimens: (1) quinapril, (2) doxazosin and quinapril combination, and (3) losartan. Gene expression profiling was performed with Affymetrix microarrays (GeneChip Rat-230A) and primary function-focused average linkage hierarchical cluster analysis. Of the 15 696 gene sequences expressed on the Affymetrix GeneChip Rat-230A, there was significant alteration in the expression of 295 (1.9%) of these transcripts in 'early' LVH and 143 (0.9%) in 'late' LVH. The predominant changes in gene expression were seen in metabolism, cell growth/proliferation, signal transduction, development and muscle contraction/cytoskeleton functional groups. Although sharing many effects on gene expression, the three treatments showed different expression profiles. Despite significant regression of LVH with treatment, 31 LVH-associated transcripts were unchanged by any of the treatment groups. Our data suggest that LVH regression does not normalize the LVH transcriptome. Therefore, regression of hypertension-induced LVH is associated with a distinct gene expression profile, suggesting the effect of both treatment and a previously unknown specific myocardial physiology after regression of LVH.

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“…More interestingly in the present context, activation of AMPK has been implicated in metabolic regulatory events during the development of cardiac hypertrophy (21). Similarly, elevated RAK activity has been shown to be a crucial component of hypertension-induced left ventricular hypertrophy (22,23), and PKN has been shown to mediate Rho GTPase activation of transcriptional activity leading to hypertrophy in cardiomyocytes (24). In addition to the cardiac-specific effects, both RAK and PKN are known to be modulators of the cytoskeleton.…”

Section: Discussionmentioning

confidence: 70%

Active Kinase Proteome Screening Reveals Novel Signal Complexity in Cardiomyopathy

Fernando

Deng²,

Pekalska

et al. 2005

Molecular & Cellular Proteomics

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Recent advances in the characterization of the phosphoproteome have been limited to measuring phosphorylation statuses, which imply but do not measure protein kinase activity directly. As such, the ability to screen, compare, and define multiple protein enzymatic activities across divergent samples remains a daunting challenge in proteomics. Here, we describe a gel-based kinase assay coupled to MS identification as an approach to map global kinase activity and assign pathway architecture to specified biologic contexts. We demonstrate the utility of this method as a platform for the comparison of proteomes based on differences in both kinase activities and for use in the de novo substrate identification for individual kinases. This approach allowed us to map the signal perturbations in the post-natal heart that were associated with activation of a myopathic cascade as mediated by the mitogen-activated protein kinase MKK6 and established the novel observation that MKK6 promotes the development of cardiomyopathy through multiple substrate interactions. Serial modification of proteins is a common mechanism for eukaryotic cellular adaptation. Within this context, protein phosphorylation is believed to be the most common form of modification. Many excellent methods describing the purification and identification of phospho-proteins are now available and have significantly contributed to our understanding of cellular regulation through signal transduction (1-4). Nevertheless, phosphorylation status alone does not unambiguously characterize the kinetic steps of signaling cascades, namely the activity of protein kinases. Indeed, there are an estimated 519 kinase-related gene products in the human genome (representing ϳ3% of the coded proteome) with a unique substrate range for each kinase (5). As such, successfully mapping these steps in any biologic model remains a daunting challenge for proteomics.In addition to the limitation imposed by current screening methodologies, the accurate reconstruction of signaling networks may also be hindered by the prevailing hypothesis that describes signaling cascades as insulated and linear events. For example, the annotation of mitogen-activated protein kinase (MAPK) 1 pathways describes a three-tier modular structure involving sequential activation from module to module (6). The p38 MAPK pathway is a typical representation of this kinase family. This pathway contains a phosphorylation sequence initiated by a MAPK kinase kinase (MKKK), which activates a MAPK kinase (MKK), which then in turn activates a MAPK (p38), with the MAPK then serving as the effector enzyme to stimulate or repress the activity of corresponding protein substrates by targeted phosphorylation (7).Considerable experimental evidence supports the basic premise of the linear MKK/p38 MAPK pathway, yet ascribing all phenotypic outcomes exclusively to the activity of the effector kinase is most likely an oversimplification. In this regard, the relationship between activation of p38 signal cascades and the development of c...

show abstract

Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure

Cited by 97 publications

References 35 publications

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

Active Kinase Proteome Screening Reveals Novel Signal Complexity in Cardiomyopathy

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