Ana Filipa Silva

Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult

The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli.

Exercise preconditioning prevents MCT-induced right ventricle remodeling through the regulation of TNF superfamily cytokines.

BACKGROUND Exercise training has been recognized as a non-pharmacological therapeutic approach in several chronic diseases; however it remains to be tested if exercise preconditioning can positively interfere with the natural history of pulmonary arterial hypertension (PAH). This is important since the majority of these patients are diagnosed at advanced stages of the disease, when right ventricle (RV) impairment is already present. OBJECTIVES In the current study, we evaluated the preventive effect of exercise preconditioning on RV failure secondary to PAH, with a focus on the signaling pathways modulated by pro-inflammatory cytokines from TNF superfamily. METHODS We analyzed the RV muscle from adult male Wistar rats exposed to a 4-week treadmill exercise training or sedentary regime, prior to the administration of monocrotaline (MCT) to induce PAH or with saline solution (controls). RESULTS Data indicate that exercise preconditioning prevented cardiac hypertrophy and RV diastolic dysfunction. At a molecular level, exercise modulated the TWEAK/NF-κB signaling axis and prevented the shift in MHC isoforms towards an increased expression of beta-MHC. Exercise preconditioning also prevented the increase of atrogin-1 expression, and induced a shift of MMP activity from MMP-9 to MMP-2 activity. CONCLUSIONS Altogether, data support exercise as a preventive strategy for the management of PAH, which is of particular relevance for the familial form of PAH that is manifested by greater severity or earlier onset.

Exercise Training in Pulmonary Hypertension and Right Heart Failure: Insights from Pre-clinical Studies

Exercise training (ExT) is widely used for the prevention and treatment of several chronic cardiovascular diseases. However, only recently it started to be recognized as safe and beneficial in pulmonary arterial hypertension. Despite the consistency of its favorable effects on exercise tolerance and quality of life, the mechanisms underlying these meaningful clinical improvements remain unclear. Current studies emphasize the exercise-induced changes on skeletal muscle but the impact of ExT at the level of the pulmonary circulation and right ventricle should not be overlooked. In this chapter, we summarize the main findings from pre-clinical studies analyzing the impact of exercise in pulmonary hypertension and right heart failure.

HMGB1 Down-Regulation Mediates Terameprocol Vascular Anti-Proliferative Effect in Experimental Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in PAH pathophysiology, displaying a hyperproliferative, and apoptotic‐resistant phenotype. In the present study, we evaluated the potential therapeutic role of terameprocol (TMP), an inhibitor of cellular proliferation and promoter of apoptosis, in a well‐established pre‐clinical model of PAH induced by monocrotaline (MCT) and studied the biological pathways modulated by TMP in PASMCs. Wistar rats injected with MCT or saline (SHAM group) were treated with TMP or vehicle. On day 21 after injection, we assessed bi‐ventricular hemodynamics and cardiac and pulmonary morphometry. The effects of TMP on PASMCs were studied in a primary culture isolated from SHAM and MCT‐treated rats, using an iTRAQ‐based proteomic approach to investigate the molecular pathways modulated by this drug. In vivo, TMP significantly reduced pulmonary and cardiac remodeling and improved cardiac function in PAH. In vitro, TMP inhibited proliferation and induced apoptosis of PASMCs. A total of 65 proteins were differentially expressed in PASMCs from MCT rats treated with TMP, some of which involved in the modulation of transforming growth factor beta pathway and DNA transcription. Anti‐proliferative effect of TMP seems to be explained, at least in part, by the down‐regulation of the transcription factor HMGB1. Our findings support the beneficial role of TMP in PAH and suggest that it may be an effective therapeutic option to be considered in the clinical management of PAH.