Vascular Aging from DNA Damage to Protection

Aging is highly associated with development of cardiovascular disease; however, the underlying mechanisms of these processes are not well understood. Recent advancements in aging research underscore the im

The Effect of the Thioether-Bridged, Stabilized Angiotensin-(1–7) Analogue Cyclic Ang-(1–7) on Cardiac Remodeling and Endothelial Function in Rats with Myocardial Infarction

Modulation of renin-angiotensin system (RAS) by angiotensin-(1–7) (Ang-(1–7)) is an attractive approach to combat the detrimental consequences of myocardial infarction (MI). However Ang-(1–7) has limited clinical potential due to its unfavorable pharmacokinetic profile. We investigated effects of a stabilized, thioether-bridged analogue of Ang-(1–7) called cyclic Ang-(1–7) in rat model of myocardial infarction. Rats underwent coronary ligation or sham surgery. Two weeks thereafter infusion with 0.24 or 2.4 μg/kg/h cAng-(1–7) or saline was started for 8 weeks. Thereafter, cardiac morphometric and hemodynamic variables as wells as aortic endothelial function were measured. The average infarct size was 13.8% and was not changed by cAng-(1–7) treatment. MI increased heart weight and myocyte size, which was restored by cAng-(1–7) to sham levels. In addition, cAng-(1–7) lowered left ventricular end-diastolic pressure and improved endothelial function. The results suggest that cAng-(1–7) is a promising new agent in treatment of myocardial infarction and warrant further research

The renin-angiotensin system, bone marrow and progenitor cells

Modulation of the RAS (renin-angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1-7) [angiotensin-(1-7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT1 receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT2 receptor (angiotensin II type 2 receptor) and the Ang-(1-7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of AngII and Ang-(1-7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications

The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice

Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.Work in the Keyes lab was funded in part by grants from the Spanish Ministry for Economy and Competitiveness (SAF2013-49082-P), La Fondation Recherche Medicale (FRM) (AJE20160635985), Fondation ARC (PJA20181208104), IDEX Attractivité-University of Strasbourg (IDEX2017), and La Fondation Schlumberger pour l'Education et la Recherche (FSER) (FSER 19-Year 2018), and ANR (ANR-19-CE13-0023-03). Work was also supported by grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d'Avenir (ANR-10-IDEX-0002-02

Red wine extract protects against oxidative-stress-induced endothelial senescence

Red wine polyphenols may preserve endothelial function during aging. Endothelial cell senescence enhances age-related endothelial dysfunction. We investigated whether RWE (red wine extract) prevents oxidative-stress-induced senescence in HUVECs (human umbilical-vein endothelial cells). Senescence was induced by exposing HUVECs to tBHP (t-butylhydroperoxide), and quantified by senescence-associated β-galactosidase staining. RWE (0-50 μg/ml) concentration dependently decreased senescence by maximally 33+- 7.1%. RWE prevented the senescence-associated increase in p21 protein expression, inhibited tBHP-induced DNA damage of endothelial cells and induced relaxation of PCAs (porcine coronary arteries). Inhibition of SIRT1 (sirtuin 1) by sirtinol partially reversed the effect of RWE on tBHP-induced senescence, whereas both the NOS (nitric oxide synthase) inhibitor L-NMMA (NG-monomethyl-L-arginine) and the COX (cyclooxygenase) inhibitor indomethacin fully inhibited it. Furthermore, incubation of HUVECs with RWE increased eNOS (endothelial NOS) and COX-2 mRNA levels as well as phosphorylation of eNOS at Ser1177. RWE protects endothelial cells from tBHP-induced senescence. NO and COX-2, in addition to activation of SIRT1, play a critical role in the inhibition of senescence induction in human endothelial cells by RWE

Phosphodiesterase 1 regulation is a key mechanism in vascular aging

Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d/-) mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1(d/-) to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; beta = 0.28, P = 2.47x10(-5)) and carotid intima-media thickness (cIMT; beta = -0.0061, P = 2.89 x 10(-5)). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy

Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/- mice.

DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model (Ercc1Δ/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1Δ/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Δ/- DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Δ/- mice. Ercc1Δ/- mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective

Local endothelial dna repair defect causes aging-resembling endothelial-specific dysfunction

We previously identified genomic instability as a causative factor for vascular aging. In the present study determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 DNA repair in mice (EC-KO mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared to WT. EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared to WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide were intact. EC-KO showed increased superoxide production compared to WT, as measured in lung tissue, rich in endothelial cells. Arterial systolic blood pressure was increased at 3 months, but normal at 5 months, at which age cardiac output was decreased. Since no further signs of cardiac dysfunction were detected this decrease might be an adaptation to prevent an increase of blood pressure. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived nitric oxide. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung

Local endothelial DNA repair defect causes aging-resembling endothelial-specific dysfunction

We previously identified genomic instability as a causative factor for vascular aging. In the present study determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 DNA repair in mice (EC-KO mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared to WT. EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared to WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide were intact. EC-KO showed increased superoxide production compared to WT, as measured in lung tissue, rich in endothelial cells. Arterial systolic blood pressure was increased at 3 months, but normal at 5 months, at which age cardiac output was decreased. Since no further signs of cardiac dysfunction were detected this decrease might be an adaptation to prevent an increase of blood pressure. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived nitric oxide. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung