Cardiac Function and Architecture Are Maintained in a Model of Cardiorestricted Overexpression of the Prorenin-Renin Receptor

The (pro)renin-renin receptor, (P)RR has been claimed to be a novel element of the renin-angiotensin system (RAS). The function of (P)RR has been widely studied in renal and vascular pathology but the cardio-specific function of (P)RR has not been studied in detail. We therefore generated a transgenic mouse (Tg) with cardio-restricted (P)RR overexpression driven by the alpha-MHC promotor. The mRNA expression of (P)RR was ∼170-fold higher (P<0.001) and protein expression ∼5-fold higher (P<0.001) in hearts of Tg mice as compared to non-transgenic (wild type, Wt) littermates. This level of overexpression was not associated with spontaneous cardiac morphological or functional abnormalities in Tg mice. To assess whether (P)RR could play a role in cardiac hypertrophy, we infused ISO for 28 days, but this caused an equal degree of cardiac hypertrophy and fibrosis in Wt and Tg mice. In addition, ischemia-reperfusion injury was performed in Langendorff perfused isolated mouse hearts. We did not observe differences in parameters of cardiac function or damage between Wt and Tg mouse hearts under these conditions. Finally, we explored whether the hypoxia sensing response would be modulated by (P)RR using HeLa cells with and without (P)RR overexpression. We did not establish any effect of (P)RR on expression of genes associated with the hypoxic response. These results demonstrate that cardio-specific overexpression of (P)RR does not provoke phenotypical differences in the heart, and does not affect the hearts’ response to stress and injury. It is concluded that increased myocardial (P)RR expression is unlikely to have a major role in pathological cardiac remodeling

Inhibition of Interleukin-6 Receptor in a Murine Model of Myocardial Ischemia-Reperfusion

Background Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). Methods CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. Results I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28 +/- 4% vs. 35 +/- 6%, p = 0.02; sham 45 +/- 6% vs. 43 +/- 4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. Conclusion Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling

The Development and Subsequent Elimination of Aberrant Peripheral Axon Projections in Semaphorin3A Null Mutant Mice

AbstractSemaphorin3A (previously known as Semaphorin III, Semaphorin D, or collapsin-1) is a member of the semaphorin gene family, many of which have been shown to guide axons during nervous system development. Semaphorin3A has been demonstrated to be a diffusible chemorepulsive molecule for axons of selected neuronal populations in vitro. Analysis of embryogenesis in two independent lines of Semaphorin3A knockout mice support the hypothesis that this molecule is an important guidance signal for neurons of the peripheral nervous system (M. Taniguchi et al., 1997, Neuron 19, 519–530; E. Ulupinar et al., 1999, Mol. Cell. Neurosci. 13, 281–292). Surprisingly, newborn Semaphorin3A null mutant mice exhibit no significant abnormalities (O. Behar et al., 1996, Nature 383, 525–528). In this study we have tested the hypothesis that guidance abnormalities that occurred during early stages of Semaphorin3A null mice development are corrected later in development. We have found that the extensive abnormalities formed during early developmental stages in the peripheral nervous system are largely eliminated by embryonic day 15.5. We demonstrate further that at least in one distinct anatomical location these abnormalities are mainly the result of aberrant projections. In conclusion, these findings suggest the existence of correction mechanisms that eliminate most sensory axon pathfinding errors early in development

AF inducibility and duration in mice subjected to sham surgery or ventricular pressure overload.

<p>A) AF inducibility and B) Duration of the longest AF episode in each mouse.</p

Ventricular pressure overload increased LVEDP and induced atrial hypertrophy and atrial dilatation.

<p>A) LVEDP (n = 15–21 per group), B) lectin staining – I sham, II TAC 8 weeks -, the ruler is 50 μm, C) quantification of the lectin staining (n = 6–7 per group), D) increased atrial weight, corrected by tibia length (n = 11–16 per group) and E) increased LA length (n = 14–23 per group). *P<0.05, **P<0.01, ***P<0.001 vs sham. ^#P<0.05, ^{# #}P<0.01, ^{# # #}P<0.001 vs TAC 4 weeks. LVEDP, left ventricle end diastolic pressure.</p

Ventricular pressure overload increased atrial mRNA expression of markers related to inflammation.

<p>A) IL-6 (n = 12–16 per group) and B) MCP-1 (n = 12–16 per group). *P<0.05, **P<0.01, ***P<0.001 vs sham. ^#P<0.05, ^{# #}P<0.01, ^{# # #}P<0.001 vs TAC 4 weeks.</p

In the left ventricle, ventricular pressure overload induced hypertrophy and fibrosis.

<p>A) Cell diameter (n = 7–8 per group) – I sham, II TAC 4 weeks, III TAC 8 weeks, IV quantification -, the ruler is 50 μm, B) Masson's trichrome staining (n = 13–18 per group) – I sham, II TAC 4 weeks, III TAC 8 weeks, IV quantification -, the ruler is 100 μm, and C) mRNA expression of ANP (n = 12–17 per group), D) skeletal α-actin (n = 12–17 per group) and E) collagen type I (n = 12–17 per group). F) representative echocardiographic images. *P<0.05, **P<0.01, ***P<0.001 vs sham. ^#P<0.05, ^{# #}P<0.01, ^{# # #}P<0.001 vs TAC 4 weeks. ANP, atrial natriuretic peptide.</p

Atrial mRNA expression levels related to hypertrophy were increased.

<p>A) ANP (n = 12–16 per group), B) BNP (n = 12–16 per group), C) GDF15 (n = 12–16 per group), D) skeletal α-actin (n = 12–13), E) Rcan1 (n = 12–16 per group). *P<0.05, **P<0.01, ***P<0.001 vs sham. ^#P<0.05, ^{# #}P<0.01, ^{# # #}P<0.001 vs TAC 4 weeks. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; GDF15, growth differentiation factor 15; Rcan1, Regulator of calcineurin 1.</p