Anna M Gumpert

Cardiovascular gene therapy for myocardial infarction.

Introduction: Cardiovascular gene therapy is the third most popular application for gene therapy, representing 8.4% of all gene therapy trials as reported in 2012 estimates. Gene therapy in cardiovascular disease is aiming to treat heart failure from ischemic and non-ischemic causes, peripheral artery disease, venous ulcer, pulmonary hypertension, atherosclerosis and monogenic diseases, such as Fabry disease. Areas covered: In this review, we will focus on elucidating current molecular targets for the treatment of ventricular dysfunction following myocardial infarction (MI). In particular, we will focus on the treatment of i) the clinical consequences of it, such as heart failure and residual myocardial ischemia and ii) etiological causes of MI (coronary vessels atherosclerosis, bypass venous graft disease, in-stent restenosis). Expert opinion: We summarise the scheme of the review and the molecular targets either already at the gene therapy clinical trial phase or in the pipeline. These targets will be discussed below. Following this, we will focus on what we believe are the 4 prerequisites of success of any gene target therapy: safety, expression, specificity and efficacy (SESE).

Leukocyte-Expressed β2-Adrenergic Receptors are Essential for Survival Following Acute Myocardial Injury

Background: Immune cell–mediated inflammation is an essential process for mounting a repair response after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune system function through &bgr;-adrenergic receptors (&bgr;ARs); however, their role in regulating immune cell responses to acute cardiac injury is unknown. Methods: Wild-type (WT) mice were irradiated followed by isoform-specific &bgr;AR knockout (&bgr;ARKO) or WT bone-marrow transplantation (BMT) and after full reconstitution underwent MI surgery. Survival was monitored over time, and alterations in immune cell infiltration after MI were examined through immunohistochemistry. Alterations in splenic function were identified through the investigation of altered adhesion receptor expression. Results: &bgr;2ARKO BMT mice displayed 100% mortality resulting from cardiac rupture within 12 days after MI compared with ≈20% mortality in WT BMT mice. &bgr;2ARKO BMT mice displayed severely reduced post-MI cardiac infiltration of leukocytes with reciprocally enhanced splenic retention of the same immune cell populations. Splenic retention of the leukocytes was associated with an increase in vascular cell adhesion molecule-1 expression, which itself was regulated via &bgr;-arrestin–dependent &bgr;2AR signaling. Furthermore, vascular cell adhesion molecule-1 expression in both mouse and human macrophages was sensitive to &bgr;2AR activity, and spleens from human tissue donors treated with &bgr;-blocker showed enhanced vascular cell adhesion molecule-1 expression. The impairments in splenic retention and cardiac infiltration of leukocytes after MI were restored to WT levels via lentiviral-mediated re-expression of &bgr;2AR in &bgr;2ARKO bone marrow before transplantation, which also resulted in post-MI survival rates comparable to those in WT BMT mice. Conclusions: Immune cell–expressed &bgr;2AR plays an essential role in regulating the early inflammatory repair response to acute myocardial injury by facilitating cardiac leukocyte infiltration.

Interleukin-10 inhibits chronic angiotensin II-induced pathological autophagy

BACKGROUND Although autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is unknown. Here we tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, leads to improve cardiac function. METHODS AND RESULTS Chronic Ang II strongly induced mortality, cardiac dysfunction in IL-10 Knockout mice. IL-10 deletion exaggerated pathological autophagy in response to Ang II treatment. In isolated cardiac myocytes, IL-10 attenuated Ang II-induced pathological autophagy and activated Akt/mTORC1 signaling. Pharmacological or molecular inhibition of Akt and mTORC1 signaling attenuated IL-10 effects on Ang II-induced pathological autophagy. Furthermore, lysosomal inhibition in autophagic flux experiments further confirmed that IL-10 inhibits pathological autophagy via mTORC1 signaling. CONCLUSION Our data demonstrate a novel role of IL-10 in regulation of pathological autophagy; thus can act as a potential therapeutic molecule for treatment of chronic heart disease.

Tiny Shuttles for Information Transfer: Exosomes in Cardiac Health and Disease

Intercellular communication mediated by exosomes, nano-sized extracellular vesicles, is crucial for preserving vascular integrity and in the development of cardiovascular and other diseases. As natural carriers of signal molecules, exosomes released from sources such as blood cells, endothelial cells, immune cells, smooth muscle cells, etc., can modify a multitude of cellular bioactivities. They do so by shuttling lipids, proteins, and nucleic acids between donor and recipient cells while circulating in body fluids and in the extracellular space. A recent surge of interest in the field of exosomal biology is in part due to the recognition that the molecules they carry can act as facilitators of both pathogenesis but can also initiate protective and rescue signaling. This mini-review describes current knowledge on exosome function in health and disease including cardiovascular disease.

The Adrenergic System and Stem Cell-Mediated Myocardial Repair

The continuous increase of average human life span is yielding a progressively older population pool. With the aging population and increasingly sedentary lifestyle, chronic cardiovascular diseases are approaching epidemic proportions in nearly all developed countries. Decline in cardiovascular performance is counteracted by the interaction of the sympathetic (adrenergic) nervous system (ANS) and the parasympathetic system. Acutely, the elevated activity of the adrenergic system will swiftly reestablish cardiac function and return to steady levels. However, a chronic manifestation of altered cardiac function is followed by prolonged and compensatory ANS hyperactivity, which over time will lead to increased pressure on the already weakened heart. Thus far, β-receptor blockade has been the main therapeutic approach with which the inhibition of the adrenergic drive has had a positive effect counteracting the progression of cardiovascular decline. With the emergence of new discoveries in stem cell research and their possible contribution to cardiac cell turnover and tissue repair, it is critical to evaluate the extent of the impact of the ANS on cardiac regeneration via the regulation of stem cells.