A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies.

In this perspective, we discussed emerging data indicating a role for Notch signalling in inherited disorders of the heart failure with focus on hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) linked to variants of genes encoding mutant proteins of the sarcomere. We recently reported an upregulation of elements in the Notch signalling cascade in cardiomyocytes derived from human inducible pluripotent stem cells expressing a TNNT2 variant encoding cardiac troponin T (cTnT-I79N+/-), which induces hypertrophy, remodelling, abnormalities in excitation-contraction coupling and electrical instabilities (Shafaattalab S et al. 2021 Front. Cell Dev. Biol. 9, 787581. (doi:10.3389/fcell.2021.787581)). Our search of the literature revealed the novelty of this finding and stimulated us to discuss potential connections between the Notch signalling pathway and familial cardiomyopathies. Our considerations focused on the potential role of these interactions in arrhythmias, microvascular ischaemia, and fibrosis. This finding underscored a need to consider the role of Notch signalling in familial cardiomyopathies which are trigged by sarcomere mutations engaging mechano-signalling pathways for which there is evidence of a role for Notch signalling with crosstalk with Hippo signalling. Our discussion included a role for both cardiac myocytes and non-cardiac myocytes in progression of HCM and DCM. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Ouabain induces nitric oxide release by a PI3K/Akt-dependent pathway in isolated aortic rings from rats with heart failure.

BACKGROUND: Ouabain occurs in nanomolar concentrations in myocardial infarction and heart failure (HF). However, the effects of ouabain in vascular function in HF conditions were not investigated yet. Therefore, we analyzed the effects of acute administration of 3 nM ouabain in isolated aortic rings from rats with HF 4 weeks after myocardial infarction. METHODS AND RESULTS: Rats were submitted to sham operation or coronary artery occlusion. In HF rats, left ventricular positive and negative derivatives of intraventricular pressure reduced and left ventricular end diastolic pressure increased. Phenylephrine responses increased in HF rings when compared with controls. Ouabain incubation for 45 minutes reduced phenylephrine-induced contraction in both groups. Endothelial removal increased more phenylephrine response in ouabain-treated rings of sham rats. Ouabain potentiated the effect of L-NAME in both groups but more in sham rats. Wortmannin increased the phenylephrine response only in HF rings. The effect of tetraethylammonium was potentiated by ouabain only in HF rings. Ouabain increased phenylephrine-stimulated nitric oxide production in rings from both groups but increased the activation of Akt only in vessels from HF rats. CONCLUSIONS: Results demonstrate that low ouabain concentration can decrease vascular reactivity of aortic rings from HF rats. Ouabain was able to increase nitric oxide production in HF rats by triggering a signal transduction PI3K/Akt-dependent pathway and increasing an endothelium-hyperpolarizing factor release.

Myocardial contractility is preserved early but reduced late after ovariectomy in young female rats.

BACKGROUND: Ovarian sex hormones (OSHs) are implicated in cardiovascular function. It has been shown that OSHs play an important role in the long term regulation of cardiac sarcoplasmic reticulum (SR) function and contractility, although early effects of OSHs deprivation on myocardial contractility have not yet been determined. This study evaluated the early and late effects of OSHs deficiency on left ventricular contractility in rats after ovariectomy. METHODS: Young female Wistar rats were divided into 3 groups (n=9-15): sham operated (Sham), ovariectomized (Ovx) and Ovx treated with estradiol (1 mg/kg, i.m., once a week) (Ovx+E2). After 7, 15, 30 and 60 days post Ovx, left ventricle papillary muscle was mounted for isometric tension recordings. The inotropic response to Ca2+ (0.62 to 3.75 mM) and isoproterenol (Iso 10-8 to 10-2 M) and contractility changes in response to rate changes (0.25 to 3 Hz) were assessed. Protein expression of SR Ca2+-ATPase (SERCA2a) and phospholamban (PLB) in the heart was also examined. RESULTS: The positive inotropic response to Ca2+ and Iso at 7, 15, and 30 days after Ovx was preserved. However, at 60 days, the Ovx group had decreased myocardial contractility which was subsequently restored with E2 replacement. The reduction in SERCA2a and increase in PLB expression observed at 60 days after Ovx were restored with E2 replacement. CONCLUSION: This study demonstrated that myocardial contractility and expression of key Ca2+ handling proteins were preserved in the early phase and reduced at long-term during OSHs deprivation.