Sarcolemmal Invaginations and Nuclear Ca2+ (p 236)
Ibarra et al reveal how calcium signals get to cardiac myocyte nuclei without interference from the cytoplasm.
Calcium signaling in the nucleus regulates several cell functions including, chromatin condensation, nuclear transport and the activation of transcription factors. However, in cardiac myocytes, where the calcium signals in the cytosol are in constant flux, it is unclear how nuclear calcium signals are separated from the cytosolic noise. Stimulation of the cell surface receptor, insulin-like growth factor 1 receptor (IGF-1R), has been known to activate nuclear calcium signaling in cardiac myocytes, but how this signal is transmitted has remained a mystery. Now Ibarra et al show that IGF-1R is localized to invaginations of the plasma membrane or T-tubules that reach right up to the nucleus. They found that components of the signaling cascade, downstream of IGF-1R, including an associated G-protein, inositol 1,4,5 triphosphate, and phospholipase C, are also localized to the nuclear region. Furthermore, IGF-1R adopted a similar location and function in embryonic and neonatal cardiac myocytes, where T-tubules are thought to be underdeveloped. The authors suggest that the newly discovered nuclear signaling function of T-tubules might be of clinical relevance as dysfunctional T-tubules are associated with heart disease and myocardial ischemic injury.
miRNA-15a/-16 in Critical Limb Ischemia (p 335)
Spinetti et al discover two microRNAs that impair function and survival of proangiogenic cells in critical limb ischemia.
Critical limb is chemia (CLI) is an advanced form of peripheral artery disease that can cause extensive tissue injury and cell death. In severe cases, amputation is the only option. To prevent the need for such drastic treatments, researchers are investigating the use of autologous bone-marrow pro-angiogenic cells (PACs) for therapy. PAC function is impaired in CLI patients, however, so Spinetti et al wanted to know why. They found that 2 microRNAs, miR-15a and miR-16, were over-expressed in PACs and were associated with impaired survival and migration of these cells. Over-expressing miR-15a and miR-16 in healthy PACs increased their rate of apoptosis and decreased migration, while suppressing expression of the miRs in patient PACs, improved cell migration. Furthermore, PACs in which miR-15a and -16 expression was repressed, improved post-ischemic blood flow and vessel density when injected into mice with limb ischemia. The authors suggest that not only could the miRs serve as biomarkers of the disease, but that repression of miR-15a and -16 might improve PAC-based therapies in patients with CLI.
Endothelin Axis in RVH (p 347)
Drugs for lowering pulmonary artery blood pressure could have detrimental effects on the heart, say Nagendran et al.
Chronic pulmonary arterial hypertension (PAH) is not, as the name might suggest, a problem restricted to the arteries of the lungs. It is also associated with decreased functioning of the right ventricle of the heart, which can ultimately lead to heart failure and death. Endothelin receptor antagonists are currently used for the treatment of PAH, but Nagendran et al suggest that despite their favorable profile, these drugs might have detrimental effects. The drugs lower blood pressure by blocking the activity of a vasoconstrictor called Endothelin-1, which is upregulated in the pulmonary arteries of patients with PAH. However, the authors show that both Endothelin-1 and the Endothelin receptor are also upregulated in the right ventricle of these patients, and in rats with PAH. In the heart, Endothelin-1 might be part of an important compensatory response to maintain contractility, the authors suggest. Indeed, ex vivo treatment of PAH model rat hearts with an Endothelin receptor antagonist reduced contractility. On the basis of these observations, they caution that direct cardiac effects of endothelin receptor antagonists should be taken into account when considering the use of these drugs to treat PAH patients.
- © 2013 American Heart Association, Inc.