ABSTRACT
The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12-/-). SM-CXCL12-/- mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12-/- mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12-/- mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.
Subject(s)
Cardiomegaly/genetics , Chemokine CXCL12/genetics , Myocardial Infarction/genetics , Receptors, CXCR/genetics , Ablation Techniques , Animals , Cardiomegaly/metabolism , Cardiomegaly/pathology , Cardiomegaly/therapy , Coronary Vessels , Disease Models, Animal , Gene Expression Regulation/genetics , Humans , Macrophages/metabolism , Macrophages/pathology , Mice , Muscle, Smooth/metabolism , Muscle, Smooth/pathology , Myocardial Infarction/pathology , Myocardial Infarction/therapy , Myocardium/metabolism , Myocardium/pathologyABSTRACT
Obesity is a well-described risk factor resulting in premature aging of the cardiovascular system ultimately limiting longevity. Premature cardiac death and aging is the hallmark of Hutchinson-Gilford syndrome (HGPS), a disease caused by defined mutations in the lamin A gene leading to a shortened prelamin A protein known as progerin. Since small amounts of progerin are expressed in healthy individuals we aimed to investigate the association of Body-Mass-Index (BMI) with respect to expression of progerin mRNA in blood samples of patient with known cardiovascular disease. In this cross-sectional retrospective analysis, 111 patients were consecutively included of which 46 were normal (BMI < 25 kg/m2) and 65 overweight (BMI ≥ 25.0 kg/m2). Blood samples were analyzed for quantitative expression of progerin mRNA. Progerin as well as high-sensitive C-Reactive Protein (hs-CRP) levels were significantly upregulated in the overweight group. Linear regression analyses showed a significant positive correlation of BMI and progerin mRNA (n = 111; r = 0.265, p = 0.005), as well as for hs-CRP (n = 110; r = 0.300, p = 0.001) and for Hb1Ac (n = 110; r = 0.336, p = 0.0003). Our data suggest that BMI strongly correlates with progerin mRNA expression and inflammation. Progerin might contribute to well described accelerated biologic aging in obese individuals.