Exacerbated atherosclerosis in progeria is prevented by progerin elimination in vascular smooth muscle cells but not endothelial cells.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by the expression of progerin, a mutant protein that accelerates aging and precipitates death. Given that atherosclerosis complications are the main cause of death in progeria, here, we investigated whether progerin-induced atherosclerosis is prevented in HGPSrev-Cdh5-CreERT2 and HGPSrev-SM22α-Cre mice with progerin suppression in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. HGPSrev-Cdh5-CreERT2 mice were undistinguishable from HGPSrev mice with ubiquitous progerin expression, in contrast with the ameliorated progeroid phenotype of HGPSrev-SM22α-Cre mice. To study atherosclerosis, we generated atheroprone mouse models by overexpressing a PCSK9 gain-of-function mutant. While HGPSrev-Cdh5-CreERT2 and HGPSrev mice developed a similar level of excessive atherosclerosis, plaque development in HGPSrev-SM22α-Cre mice was reduced to wild-type levels. Our studies demonstrate that progerin suppression in VSMCs, but not in ECs, prevents exacerbated atherosclerosis in progeroid mice.

Coronary and carotid artery dysfunction and KV7 overexpression in a mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels in non-HGPS individuals. Although HGPS patients die predominantly from myocardial infarction and stroke, the mechanisms that provoke pathological alterations in the coronary and cerebral arteries in HGPS remain ill defined. Here, we assessed vascular function in the coronary arteries (CorAs) and carotid arteries (CarAs) of progerin-expressing LmnaG609G/G609G mice (G609G), both in resting conditions and after hypoxic stimulus. Wire myography, pharmacological screening, and gene expression studies demonstrated vascular atony and stenosis, as well as other functional alterations in progeroid CorAs and CarAs and aorta. These defects were associated with loss of vascular smooth muscle cells and overexpression of the KV7 family of voltage-dependent potassium channels. Compared with wild-type controls, G609G mice showed reduced median survival upon chronic isoproterenol exposure, a baseline state of chronic cardiac hypoxia characterized by overexpression of hypoxia-inducible factor 1α and 3α genes, and increased cardiac vascularization. Our results shed light on the mechanisms underlying progerin-induced coronary and carotid artery disease and identify KV7 channels as a candidate target for the treatment of HGPS.

Vascular smooth muscle cell aging: Insights from Hutchinson-Gilford progeria syndrome / Envejecimiento de las células del músculo liso vascular: conclusiones derivadas del síndrome de progeria de Hutchinson-Gilford

Vascular smooth muscle cells (VSMCs) constitute the principal cellular component of the medial layer of arteries and are responsible for vessel contraction and relaxation in response to blood flow. Alterations in VSMCs can hinder vascular system function, leading to vascular stiffness, calcification and atherosclerosis, which in turn may result in life-threatening complications. Pathological changes in VSMCs typically correlate with chronological age; however, there are certain conditions and diseases, such as Hutchinson-Gilford progeria syndrome (HGPS), that can accelerate this process, resulting in premature vascular aging. HGPS is a rare genetic disorder characterized by severe VSMC loss, accelerated atherosclerosis and death from myocardial infarction or stroke during the adolescence. Because experiments with mouse models have demonstrated that alterations in VSMCs are responsible for early atherosclerosis in HGPS, studies on this disease can provide insights into the mechanisms of vascular aging and assess the relative contribution of VSMCs to this process.(AU)

Las células del músculo liso vascular (CMLV) constituyen el principal componente celular de la capa medial arterial, siendo responsables de la contracción y relajación de los vasos en respuesta al flujo sanguíneo. Las alteraciones en CMLV dificultan la función vascular, generan rigidez vascular, calcificación y aterosclerosis, pudiendo resultar en complicaciones mortales. Cambios patológicos en CMLV suelen correlacionarse con la edad cronológica; sin embargo, existen afecciones y enfermedades, como el síndrome de progeria de Hutchinson-Gilford (HGPS), que pueden acelerar este proceso, provocando envejecimiento vascular prematuro. El HGPS es un trastorno genético raro caracterizado por una pérdida grave de CMLV, aterosclerosis acelerada y muerte por infarto de miocardio o ictus durante la adolescencia. Experimentos con modelos de ratón demostraron que las alteraciones en CMLV son responsables de la aterosclerosis temprana en HGPS. Por tanto, estudios sobre esta enfermedad pueden proporcionar información sobre los mecanismos del envejecimiento vascular y caracterizar la contribución de las CMLV.(AU)

Vascular smooth muscle cell aging: Insights from Hutchinson-Gilford progeria syndrome.

Vascular smooth muscle cells (VSMCs) constitute the principal cellular component of the medial layer of arteries and are responsible for vessel contraction and relaxation in response to blood flow. Alterations in VSMCs can hinder vascular system function, leading to vascular stiffness, calcification and atherosclerosis, which in turn may result in life-threatening complications. Pathological changes in VSMCs typically correlate with chronological age; however, there are certain conditions and diseases, such as Hutchinson-Gilford progeria syndrome (HGPS), that can accelerate this process, resulting in premature vascular aging. HGPS is a rare genetic disorder characterized by severe VSMC loss, accelerated atherosclerosis and death from myocardial infarction or stroke during the adolescence. Because experiments with mouse models have demonstrated that alterations in VSMCs are responsible for early atherosclerosis in HGPS, studies on this disease can provide insights into the mechanisms of vascular aging and assess the relative contribution of VSMCs to this process.

Isolation of Mouse Aortic RNA for Transcriptomics.

Aging is associated with alterations in the arterial wall that promote vascular disease development and its clinical manifestations, including myocardial infarction, stroke, and arterial dissection. The arterial wall is comprised of three layers, intima, media and adventitia, each with distinct cellular composition and function, which can therefore contribute differently to vascular disease initiation and progression. Hence, studying transcriptomic alterations, either in the entire arterial wall or separately in the three arterial layers, can aid in disentangling the etiopathology of vascular disease and thus pave the way for innovative treatments. This chapter describes protocols for total RNA extraction from complete mouse aorta and separately from intima, media, and adventitia layers for subsequent transcriptomic analysis.

Genomic instability in the naturally and prematurely aged myocardium.

Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of Ercc1, a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson-Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in Ercc1 cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.

Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson-Gilford Progeria Syndrome with Ldlr Deficiency.

Hutchinson-Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid LmnaG609G/G609G mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr-/- mice, a commonly used preclinical atherosclerosis model. Ldlr-/-LmnaG609G/G609G mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr-/-LmnaG609G/G609G mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr-/-LmnaG609G/G609G mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr-/-LmnaG609G/G609G mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies.

Non-coding RNAs: update on mechanisms and therapeutic targets from the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart.

Vast parts of mammalian genomes are actively transcribed, predominantly giving rise to non-coding RNA (ncRNA) transcripts including microRNAs, long ncRNAs, and circular RNAs among others. Contrary to previous opinions that most of these RNAs are non-functional molecules, they are now recognized as critical regulators of many physiological and pathological processes including those of the cardiovascular system. The discovery of functional ncRNAs has opened up new research avenues aiming at understanding ncRNA-related disease mechanisms as well as exploiting them as novel therapeutics in cardiovascular therapy. In this review, we give an update on the current progress in ncRNA research, particularly focusing on cardiovascular physiological and disease processes, which are under current investigation at the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. This includes a range of topics such as extracellular vesicle-mediated communication, neurohormonal regulation, inflammation, cardiac remodelling, cardio-oncology as well as cardiac development and regeneration, collectively highlighting the wide-spread involvement and importance of ncRNAs in the cardiovascular system.

Biological Versus Chronological Aging: JACC Focus Seminar.

Aging is the main risk factor for vascular disease and ensuing cardiovascular and cerebrovascular events, the leading causes of death worldwide. In a progressively aging population, it is essential to develop early-life biomarkers that efficiently identify individuals who are at high risk of developing accelerated vascular damage, with the ultimate goal of improving primary prevention and reducing the health care and socioeconomic impact of age-related cardiovascular disease. Studies in experimental models and humans have identified 9 highly interconnected hallmark processes driving mammalian aging. However, strategies to extend health span and life span require understanding of interindividual differences in age-dependent functional decline, known as biological aging. This review summarizes the current knowledge on biological age biomarkers, factors influencing biological aging, and antiaging interventions, with a focus on vascular aspects of the aging process and its cardiovascular disease related manifestations.

Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin-driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E-deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC-specific progerin expression. This stress pathway was also activated in HGPS patient-derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC-specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging-dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A.