Vascular Smooth Muscle Cell-Specific Progerin Expression Provokes Contractile Impairment in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that Is Ameliorated by Nitrite Treatment

Abstract

Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid Lmna G609G/G609G mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined Lmna LCS/LCS Tie2Cre tg/+ and Lmna LCS/LCS Sm22αCre tg/+ mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare genetic disease characterized by accelerated aging and death in adolescence [5][6][7][8][9]. HGPS children have impaired postnatal growth, lipodystrophy, alopecia, pigmented and wrinkled skin, and skeletal dysplasia. They also develop generalized atherosclerosis, arterial stiffness and calcification, electrocardiographic abnormalities, and ventricular diastolic dysfunction and die prematurely at an average age of 14.6 years mainly due to myocardial infarction, stroke, or heart failure [7,10,11]. HGPS is caused by a heterozygous de novo point mutation in the LMNA gene, which encodes the nuclear proteins lamin A and C (A-type lamins) [12,13]. This synonymous mutation activates a cryptic splice donor site that removes 150 nucleotides from exon 11, causing the synthesis of progerin [12,13]. This truncated form of prelamin A is expressed ubiquitously and acts in a dominant-negative manner, causing alterations in many essential nuclear functions, including nuclear structure, gene transcription, signal transduction, DNA damage repair, chromatin organization, mechanosensing, and proliferation [14,15]. Aside from its role in HGPS, progerin is detectable at low levels in several tissues during normal aging, including atherosclerotic coronary arteries, suggesting a role in physiological aging [11,[16][17][18][19].Homozygous Lmna-null mice lacking A-type lamins develop to term without exhibiting overt anomalies, but they develop skeletal muscle dystrophy and dilated cardiomyopathy soon after birth and are all death by the eight week [20]. Interest...

Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging

“…Reduction of DNA repair capacity by targeted mutation of Lmna in VSMC, the gene that is responsible for accelerated-aging in Hutchinson–Gilford progeria, causes hypocontraction in mice. Interestingly, this aging feature can be counteracted by increased dietary nitrites [ 22 ]. Reduced vascular stiffness was proposed as a mechanism.…”

“…Disturbed vasoconstriction is another feature of age-related vasomotor changes [6,[20][21][22]. KCl was chosen to study alterations in contractility because it is free of receptor-mediated signaling.…”

“…In addition, we studied the fate of signaling through NO and endothelium-derived hyperpolarization (EDH). As a secondary objective we also studied contractile responses to KCl, which tend to be decreased in aging mice and humans [6,[20][21][22].…”

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

“…The thoracic aorta of ≈14-week-old Lmna G609G/G609G mice shows no evidence of VSMC loss but does show reduced numbers of smooth muscle fibers (measured by hematoxylin staining) and increased deposition of medial collagen [ 51 ]. Moreover, vessel contraction in response to phenylephrine and potassium chloride is impaired in thoracic aorta segments from these progeroid mice [ 50 , 56 ], and this effect is not rescued by collagen disruption after collagenase treatment [ 50 ]. In line with this evidence of progressive damage, dysfunction, and dedifferentiation of VSMCs in Lmna G609G/G609G mice, atheroprone Apoe −/− Lmna G609G/G609G mice show VSMC depletion in the aortic arch at 16 weeks of age but not at 8 weeks [ 53 ].…”

Cells in Cardiovascular Disease: Using Diversity to Confront Adversity

“…For instance, Park et al found that gastrin releasing peptide (GRP) diminished calcification in cultured vascular smooth muscle cells (VSMC), and its inhibition reverted the phosphate-induced calcium deposition in rodent models [ 19 ]. By using models of accelerated aging, Del Campo et al [ 20 ] identified VSMC as the main cellular type causing contractile impairment in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS), and reported the beneficial effect of nitrite treatment. The impairment of vascular contractility is a part of the structural and functional alterations of the cardiovascular system in both physiological and premature aging, which in progeria patients, leads to accelerated arterial stiffness and atherosclerosis, and exaggerated CVD [ 21 ].…”