Notch1 in Bone Marrow–Derived Cells Mediates Cardiac Repair After Myocardial Infarction

Abstract

Background The signaling mechanisms that regulate the recruitment of bone marrow (BM)-derived cells to the injured heart are not well known. Notch receptors mediate binary cell fate determination and may regulate the function of BM-derived cells. However, it is not known whether Notch1 signaling in BM-derived cells mediates cardiac repair following myocardial injury. Methods and Results Mice with postnatal cardiac-specific deletion of Notch1 exhibit similar infarct size and heart function following ischemic injury as control mice. However, mice with global hemizygous deletion of Notch1 (N1+/−) developed larger infarct size and worsening heart function. When the BM of N1+/− mice were transplanted into wild-type (WT) mice, infarct size and heart function were worsened and neovascularization in the infarct border area was reduced compared to WT mice transplanted with WT BM. In contrast, transplantation of WT BM into N1+/− mice lessened the myocardial injury observed in N1+/− mice. Indeed, hemizygous deletion of Notch1 in BM-derived cells leads to decreased recruitment, proliferation, and survival of mesenchymal stem cells (MSC). Compared to WT MSC, injection of N1+/− MSC into the infarcted heart leads to increased myocardial injury, whereas injection of MSC overexpressing Notch intracellular domain leads to decreased infarct size and improved cardiac function. Conclusions These findings indicate that Notch1 signaling in BM-derived cells is critical for cardiac repair, and suggest that strategies that increase Notch1 signaling in BM-derived MSC could have therapeutic benefits in patients with ischemic heart disease.

Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

“…In this respect, it should be considered that AAV vectors are outstanding tools for gene transfer into postmitotic cells and that their efficiency, in the heart, increases with terminal cardiomyocyte differentiation. 26 Thus, although our experiments rule out a direct effect of Notch pathway reactivation in driving adult cardiomyocyte proliferation in vitro and in vivo, they still remain compatible with the possibility that Notch signaling in adults hearts might exert beneficial effects in other cell types, such as in epicardial cells, 18 mesenchymal stromal cells, 16 bonemarrow-derived cells, 60 or cardiomyocyte precursors derived from cardiac stem cells. 9,17 Reactivation of Notch1 expression after MI in α-myosin heavy chain-mER-CremER transgenic mice showed a positive effect, which was mainly attributed to the preservation of cardiomyocyte viability and the stimulation of angiogenesis, with no evidence of a major regenerative effect.…”

Olmesartan Attenuates Cardiac Remodeling Through DLL4/Notch1 Pathway Activation in Pressure Overload Mice

“…[25][26][27][28] Previous studies showed crosstalks between Notch and other vascular signaling pathways in regulating arteriogenesis. 11 In tumor angiogenesis, inactivation of DLL4/Notch1 signaling inhibits tumor growth by promoting nonproductive angiogenesis. 7,29,30 Notch1 activation can induce neovascularization in the infarcted hearts and inactivation of Notch signaling leads to the inhibition of postnatal vasculogenesis in hindlimb ischemia.…”

“…[6][7][8] Notch1 receptor has been speculated to exert cardioprotection in injured myocardium, by controlling the cardiac adaptation to stress, enhancing myocyte survival, promoting precursor proliferation, and reducing fibrosis. 6,[9][10][11] DLL4/Notch1 activation is a requisite for the survival of hypertrophic myocardium and for the regeneration of damaged tissue. 6,9,12 On the contrary, inhibition of Notch1 signaling exacerbates cardiac hypertrophy, fibrosis, apoptosis, and dysfunction.…”

TRPC6, a potential novel target for enhancing cardiac repair of bone marrow mesenchymal stem cells

“…It has been well documented that bone marrow mesenchymal stem cells (BMSCs) therapy has been widely applied in ischemic diseases such as myocardial and hepatic ischemia, through promotion of angiogenesis and suppression of apoptosis [1,2]. Meanwhile, BMSCs transplantation has been demonstrated to be an effective therapy for cerebrovascular diseases, which could promote endogenous neurogenesis and behavioral recovery [3].…”

“…Once validated, TRPC6 may serve as a novel target in prevention and cure of MI. Keywords: Coronary Correlation Epicardial Myocardial blush TIMI frame count Videodensitometry TIMI frame count (TFC), was introduced in the early 1990s, as a method to assess the efficacy of thrombolysis and risk stratification in acute myocardial infarction (AMI) [1]. TFC proved to be a simple, reproducible, quantitative and objective method to evaluate epicardial flow not only in acute coronary syndrome settings, but in stable conditions with microvascular dysfunction, as well [2].…”