Stefanie Dimmeler

MicroRNA-29 in aortic dilation: implications for aneurysm formation [Molecular Medicine]

Rationale: Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown. Objective: We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies. Methods and Results: Expression profiling of aortic tissue of young versus old mice identified several age-associated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4R/R mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (n=79) or tricuspid aortic valves (n=30). Finally, LNA-modified antisense oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice. Conclusion: In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity.

A novel cardiac extracorporeal shock wave for enhancing the efficacy of cell therapy

Targeted therapy can maximize therapeutic efficiency and minimize the side effects of drug treatments, especially for cancer and cardiovascular disease. In previous in-vitro experiments, it was shown that shock wave (SW) application can change the permeability of cell membranes for tumor therapy. Similarly, in animal studies, extracorporeal SWs were proven to increase expression of growth and homing factors like SDF-1 and vascular endothelial growth factor (VEGF) within a targeted ischemic tissue. This pretreatment increased the homing and neovascularization following application of bone marrow-derived mononuclear cells (BMC). In a randomized, double blinded, placebo-controlled clinical trial, 103 patients were recruited with stable chronic post-infarction heart failure (CHF). The goal of this work was to demonstrate improved recovery of left ventricular contractile function (LVEF) by combining targeted SW application with subsequent BMC administration. Results showed that the shock wavefacilitated intrac...

Cytotoxicity, Apoptosis, and Nitric Oxide

Cell death plays an important physiological role during development and the turnover of cells in the tissue. However, the induction of excessive cell death by injury also contributes to various pathophysiological disorders. Toxic insults or ischemic injury can lead to the destruction of cells. Such cytotoxic effects are often the consequence of necrotic cell death. Necrotic processes are characterized by the disruption of cell homeostasis, energy depletion, organelle swelling, and random catalytic processes (1). The increase of plasma membrane permeability further leads to the release of the cell content into the extracellular milieu, which consequently evokes an inflammatory response. The induction of necrotic cell death during embryonal development or essential tissue cell turnover would have detrimental effects. Therefore, another kind of cell death was proposed to mediate these processes, which was initially termed “shrinkage necrosis” or “apoptosis” (Greek; apo:- apart; -ptosis:falling), referring to the cell death responsible for the falling of leaves in autumn (2). Given its strictly regulated nature, this kind of cell death was also termed “programmed cell death.” Apoptosis or programmed cell death refers to the morphological alterations exhibited by “actively” dying cells that include cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation (3). Finally, apoptotic cells expose specific molecules on the surface to initiate phagocytosis either by resident cells or by specialized phagocytes, thus ensuring that no intracellular material is released into the tissue and, therefore, preventing an inflammatory reaction (4). Thus, the apoptotic process is often referred to as “silent cell death.”