The adult mammalian heart is thought to be a terminally differentiated organ given the postmitotic nature of cardiomyocytes. Consequently, the potential for cardiac repair through cardiomyocyte proliferation is extremely limited. Low-density lipoprotein receptor-related protein 6 (LRP6) is a Wnt co-receptor that is required for embryonic heart development. In this study we investigated the role of LRP6 in heart repair through regulation of cardiomyocyte proliferation. Lrp6 deficiency increased cardiomyocyte cell cycle activity in neonatal, juvenile and adult mice. Cardiomyocyte-specific deletion of Lrp6 in the mouse heart induced a robust regenerative response after myocardial infarction (MI), led to reduced MI area and improvement in left ventricular systolic function. In vivo genetic lineage tracing revealed that the newly formed cardiomyocytes in Lrp6-deficient mouse hearts after MI were mainly derived from resident cardiomyocytes. Furthermore, we found that the pro-proliferative effect of Lrp6 deficiency was mediated by the ING5/P21 signaling pathway. Gene therapy using the adeno-associated virus (AAV)9 miRNAi-Lrp6 construct promoted the repair of heart injury in mice. Lrp6 deficiency also induced the proliferation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Our study identifies LRP6 as a critical regulator of cardiomyocyte proliferation, which may lead to the development of a novel molecular strategy to promote myocardial regeneration and repair.
Hypertension (HTN) has now been associated with cognitive impairment and considered as one of the risk factors for mild cognitive impairment (MCI). To investigate whether there is neuronal mechanism, HTN was induced in C57BL/6j male mice (~22 weeks) by DOCA-salt treatment (DS, 1.4mg/g+1%NaCl, 28 days), a neurogenic model. Firstly, BP was monitored by tail-cuff (sham vs. DS: SBP= 116.1±7.6 vs. 145.0±8.2 mmHg). Then, behavioral study was performed to assess the cognitive function (CFN). In whole, compared to sham, the DS mice performed worse in all 4 tasks, including object location recognition (before vs. after: NLR%= 29.34±13.73 vs. -20.81±10.70), novel object recognition (NOR%= 48.60±22.62 vs. 9.09±25.50), Barnes maze (latency T= 26.55±16.52 vs. 116.80±57.67s), and nesting (score= 4.00±0.92 vs. 2.43±1.55). Later, CBF was measured by laser doppler. The rise of CBF upon whisker-stimulation (WS) was lower in the DS mice (27.83±13.86 vs. 51.12±18.22 PU), while their basal CBF was not affected, suggesting that DS-induced MCI could be related to impairment of neuro-vascular coupling (NVC). Previously, we have showed the overactivation of brain renin-angiotensin system (RAS) in the onset of DS HTN. To identify the possible contribution from brain RAS, neuronal AT 1a R were deleted (AT1N). In AT1N mice, DS-related impairments in CFN and NVC were attenuated, as evidenced by higher nesting scores (AT1N+DS vs. NT+DS: 3.75±1.89 vs. 2.43±1.55 ), better performance in Barnes maze (61.28±54.47 vs. 116.80±57.67 s) and grater augment in CBF upon WS (41.49±10.65 vs. 27.83±13.86 PU), compared to NT. Through LTP recording in CA1 neurons using both field and whole-cell modes, we identified that activation of neuronal AT 1 R could contribute directly to the development of MCI, thereby neuronal AT 1 R was selectively knocked down in the hippocampus of NT mice (AT1hN). After DS treatment, AT1hN showed no difference in SBP compared with the sham NT (149.0±14.7 vs. 150.4±6.9 mmHg), while their CFN showed improvement in both NOR and Barnes maze (NOR%= 11.70±25.78 vs. -10.15±42.60; latency T= 71.72±47.60 vs. 113.70±65.64 s). In summary, our data suggest that neuron-expressing AT 1 R could participate in the onset of hypertension-associated MCI via both vascular and neural mechanisms.
Hypertension has now been closely associated to cognitive impairment, due to its contribution to cerebrovascular dysfunction. To investigate whether there is neuronal mechanism, hypertension was induced in C57BL/6j male mice (6 months) by DOCA‐salt treatment (1.5 mg/g, s.c., 28 days). Firstly, behavioral study, which contains object location behavioral task, novel object recognition, Barnes maze, and nesting score test, was performed to assess cognitive function, meanwhile, blood pressure (BP) was monitored by tail‐cuff device. In NT (non‐transgenic) mice, DOCA+1%NaCl increases BP significantly, before vs. after DOCA (systolic BP): 114.8 ±0.94 vs. 133.7 ±3.3 mmHg. In whole, compared to sham controls, the treated NT mice performed worse in all four behavioral tests, indicating cognition decline after DOCA‐salt treatment. Later, brain tissues were collected to evaluate possible degenerative alterations in neurons by transmission electron microscope (TEM) imaging, Golgi‐Cox staining, fluorescence‐activated cell sorting (FACS) and qRT‐PCR. It was shown via the TEM that DOCA‐salt hypertension induces mitochondrial damage and morphological changes in prefrontal cortical neurons, meanwhile, Golgi‐Cox staining revealed decreased numbers of dendritic spines, suggesting the onset of neurodegeneration in DOCA‐salt hypertension. In both prefrontal cortex and hippocampus, the mRNA levels of BDNF (brain‐derived neurotrophic factor) and PI4KIIIβ (phosphatidylinositol 4‐kinase IIIβ) were found to be significantly lower in hypertensive NT mice. Using FACS, neurons were sorted from those regions, then analyzed via qRT‐PCR, which identified that the downregulated expression of PI4KIIIβ takes place in neurons. Using laser speckle contrast imaging system, we detected only decreased functional hyperemia, but no impairment in basal cerebral blood flow of the hypertensive mice, suggesting that the neurodegeneration is not caused by cerebral ischemia. We previously demonstrated that neuronal angiotensin type 1 receptors (AT1R) plays a pivotal role in the maintenance of neurogenic hypertension, and here we hypothesized that activation of AT1R could also exacerbate hypertension‐induced reduction in neuronal function. Particularly, in the hippocampal CA1 of adult mice, treatment of angiotensin II (Ang‐II, 500 nM, bath application) induces a significant inhibition in the induction of long‐term potentiation (LTP), while pre‐treatment with losartan (5 μM, 15 min), the AT1R antagonist, can efficiently block this Ang‐II‐induced inhibition, supporting the involvement of neuronal AT1R. Indeed, in mice with selective deletion of neuronal AT1aR, DOCA‐salt‐induced neurodegeneration was attenuated, as evidenced by significantly higher mRNA levels of cortical BDNF and PI4KIIIβ, compared with the NT. In summary, our data suggest that neuron‐expressing AT1R participates in the development of hypertension‐associated cognitive impairment, independently of vascular AT1R.
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