The renin-angiotensin-aldosterone system (RAAS) is critical in regulating systemic blood pressure, water and electrolyte balance, and pituitary gland hormones. These physiologies appear to be primarily mediated by the angiotensin II/AT(1) receptor subtype system. Overstimulation of this system can predispose cardiovascular disease (CVD) characterized by excessive vasoconstriction, fibrosis, and cardiac remodeling. If untreated, the patient typically displays a continuum of pathophysiologic conditions progressing from atherosclerosis to left ventricle hypertrophy (LVH), coronary thrombosis, myocardial infarcts, with heart failure as an endpoint. Intervention with antihypertensive therapy is necessary to inhibit this progression. RAAS blocking drugs appear to be the most effective approach. Diastolic heart failure patients benefit from treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin AT(1) receptor blockers (ARBs). Elderly CVD patients evidence age-related changes in body composition that alter the distribution and half-life of medications, thus presenting special challenges to treatment. The presence of comorbidities such as diabetes, renal dysfunction, liver insufficiency further complicates any therapeutic strategy. In addition, noncompliance because of cognitive impairment, depression, confusion due to the complexity of dose regimens, and lack of an appropriate social support system can disrupt positive outcome. The present review discusses the roles of an overactive RAAS and sympathetic nervous system as primary contributors to CVD. In addition, treatment strategies are discussed, focusing on middle aged and elderly hypertensive and heart failure patients.
"Indeed, inactivation of ROCK via angiotensin II inhibition prevents stress fiber formation and hypertrophy in a cell line derived from rat heart myoblasts (Kim et al., 2013). Finally, the role of Fasudil as a potent vasodilator (Fukumoto et al., 2005) may also alleviate the fibrosis-dependent vasoconstriction of SMA hearts (reviewed in Wright et al., 2008). While it is tempting to hypothesize that overexpression of activated RhoA/ROCK during SMA pathogenesis is responsible for the observed cardiac defects, assessment of this pathway in SMA hearts and evaluation of the effects of Y-27632 and Fasudil on cardiac function and pathology have unfortunately not been performed . "
[Show abstract][Hide abstract] ABSTRACT: Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.
Frontiers in Neuroscience 08/2014; 8. DOI:10.3389/fnins.2014.00271 · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RESUMO A hipertrofia ventricular esquerda (HVE) representa uma resposta adaptativa do coração à hipertensão arterial. Embora considerada compensatória, a HVE é um preditor independente de maior morbimortalidade cardiovascular. Em concordância com essas observações, diversas evidências clínicas e epidemiológicas demonstraram que a HVE é um importante fator de risco para o desenvolvimento de insuficiência cardíaca (IC) sistólica e diastólica. Além da massa miocárdica, a geometria ventricular também influen - cia o desenvolvimento de IC. Nesse contexto, a hipertrofia concêntrica corresponde ao padrão geométrico que tem sido mais associado à progressão para IC. Diversos meca- nismos têm sido propostos para explicar a transição de HVE para IC. Entre eles, destacam-se as alterações na micro e na macrocirculação coronária e a fibrose intersticial, as quais comprometem o suprimento de oxigênio e nutrientes para os miócitos cardíacos e impedem um desempenho mecânico satisfatório dessas células. Esses fatores modificam tanto a contratilidade quanto o relaxamento miocárdico, sugerindo que as disfunções sistólica e diastólica relacionadas à HVE podem representar um continuum. Por outro lado, eventos isquêmicos também podem precipitar o desenvolvimento de IC, demonstrando que a progressão de HVE para IC tem origem multifatorial e é resultante de uma complexa interação entre fatores intrínsecos e extrínsecos ao miocárdio. PALAVRAS-CHAVE Hipertrofia ventricular esquerda, insuficiência cardíaca, ecocardiografia, disfunção ventricular esquerda. ABSTRACT Left ventricular hypertrophy (LVH) is an adaptive respon- se to systemic hypertension. Nevertheless, it has been extensively demonstrated that LVH is an independent predictor of increased cardiovascular risk and heart failure (HF) development. In this regard, not only myocardial mass but also left ventricular geometric pattern have been shown to influence left ventricular performance. For instance, concentric hypertrophy displays the major risk to HF progression, especially to its diastolic form. Conversely, several mechanisms have been proposed to explain the transition from LVH to overt HF. They include coronary micro and macrovascular changes and myo- cardial interstitial fibrosis, which may lead to a reduced supply of oxygen and nutritional factors to myocytes and to a mechanical impairment of myocyte function. These alterations impair either contractile or relaxing performance, thus suggesting that LVH-related systolic and diastolic dysfunction may represent a continuum. On the other hand, coronary atherothrombotic events may also precipitate left ventricular dysfunction, demonstra- ting that transition from LVH to HF is a complex process that results from the interaction between extrinsic and intrinsic myocardial factors.
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