Pharmacogenetic Associations of MMP9 and MMP12 Variants with Cardiovascular Disease in Patients with Hypertension

MMP-9 and -12 function in tissue remodeling and may play roles in cardiovascular disease (CVD). We assessed associations of four MMP polymorphisms and three antihypertensive drugs with cardiovascular outcomes.Hypertensives (n = 42,418) from a double-blind, randomized, clinical trial were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatment (mean follow up, 4.9 years). The primary outcome was coronary heart disease (CHD). Secondary outcomes included combined CHD, all CVD outcomes combined, stroke, heart failure (HF), and mortality. Genotype-treatment interactions were tested. = 0.015). for CHD and composite CVD. The data suggest that these genes may provide useful clinical information with respect to treatment decisions

Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR−/− mice

PPAR(δ) (peroxisome proliferator-activated receptor δ) mediates inflammation in response to lipid accumulation. Systemic administration of a PPAR(δ) agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPAR(δ) in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPAR(δ) expression in these cells may mitigate atherogenesis. To advance this finding forward to potential clinical translation through hematopoietic stem cell transplantation-based gene therapy, we employed a microRNA (miRNA) approach to knock down PPAR(δ) expression in bone marrow cells followed by transplantation of the cells into LDLR −/− mice. We found that knockdown of PPAR(δ) expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPAR(δ) led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β and IL-6. Expression of CCR2, a receptor for MCP-1, was also decreased. The downregulation of pro-inflammatory factors is consistent with significant reduction of macrophage presence in the lesions, which may also be attributable to elevation of ABCA1 (ATP-binding cassette, subfamily A, member 1) and depression of adipocyte differentiate-related protein. Furthermore, the abundance of both MCP-1 and matrix metalloproteinase-9 proteins was reduced in plaque areas. Our results demonstrate that miRNA-mediated PPAR(δ) knockdown in hematopoietic cells is able to ameliorate atherosclerosis

Macrophage metalloprotease (MMP)-12 as a cardiovascular biomarker

Cardiovascular diseases (CVD) worldwide represent the principal cause of death. Thus, the challenge to identify novel and clinically useful biomarkers of CVD risk has focused the attention over the last years. Atherosclerosis (ATS) is one of the major causes of CVD. ATS is an inflammatory multifactorial disease, in which the complex interaction between immune cells and inflammatory mediators drives the growth of atherosclerotic lesions and their progression toward complications. Taking into account the great number of molecules and cells involved, over the time several markers have been evaluated, including inflammatory mediators, acute phase response proteins, blood cells and proteins implicated in lipid metabolism. The study of these molecules has significantly contributed to improve the knowledge about the immune-inflammatory mechanisms involved in the pathogenesis of ATS; however, they did not often represent useful biomarkers in the clinical practice due to their poor specificity. The contribution of matrix metalloproteinases (MMPs) to CVD has been extensively reported, whereas their role as biomarkers and prognostic factors is not fully elucidated. Here we point out the role of MMP-12 as biomarker of CVD