AKT2 Protects Against AAD (p 618)
The protein kinase AKT2 is protective against aortic aneurysm, report Shen et al.
Progressive degeneration and weakening of the aortic walls can lead to dilation (aneurysm), tearing (dissection), and even rupturing of the aorta. Although aortic aneurysms are associated with a loss of smooth muscle cells and destruction of the extracellular matrix in the artery wall, little else is known about the pathology of this potentially deadly condition. The protein kinase AKT2 is known to promote the proliferation and migration of smooth muscle cells in vessel walls. While this activity can be harmful in conditions such as atherosclerosis—where it may cause vessel narrowing—Shen and colleagues wondered if it could protect against the weakening of the aortic wall. They found that mice lacking AKT2 had thinner aortic walls and when treated with angiotensin II were more prone to aortic aneurysm, dissection, and rupture. Furthermore, aortic tissues taken from patients with aneurysms and dissections exhibited lower levels of AKT2 than control tissues. Rather than promoting smooth muscle cell proliferation, as initially thought, however, AKT2 appears to protect aortic walls by not only inhibiting production of MMP-9, an enzyme that breaks down extracellular matrices, but also by promoting the production of TIMP-1, an inhibitor of MMP-9. Thus both AKT2 and these downstream factors could be targets for the development of novel aneurysm therapies.
Dihydropyridines Activate Ca2+-sensing Receptors (p 640)
Drugs commonly used to treat pulmonary arterial hypertension could actually be exacerbating the condition, say Yamamura et al.
While dihydropyridine calcium channel blockers, such as nifedipine and nicardipine, are often prescribed for pulmonary arterial hypertension (PAH), they are effective in only 15–20% of patients, who are referred to as vasoreactive responders. These drugs work by blocking calcium channels in vascular smooth muscle cells, which lowers cytosolic calcium levels and prevents contraction. Yamamura et al have discovered that these drugs also activate a second type of calcium protein in smooth muscle cells called the calcium sensing receptor (CaSR). And they show that activation of this receptor actually increases cytosolic calcium. In normal vascular smooth muscle cells the expression level of CaSR proteins is too low for this counteraction to be problematic, which explains why such drugs are successful vasodilators for many other conditions. In PAH patient smooth muscle cells, however, CaSR proteins tend to be upregulated. The findings not only offer an explanation as to why so few PAH patients respond to dihydropyridine channel blockers, but they also suggest that by raising smooth muscle cell calcium levels, these drugs could actually worsen PAH. Alternative options, such as non-dihydropyridine calcium channel blockers and CaSR blockers could prove to be more effective for the treatment of PAH, say the authors.
Titin Phosphorylation by CaMKII (p 664)
CaMKII kinase regulates elasticity of the cardiomyocyte protein titin, show Hamdani et al.
Titin is a large elastic protein found in cardiomyocytes that controls the stiffness of these cells, and as a result the myocardium as a whole. The protein is phosphorylated by many different kinases, and Hamdani and colleagues now add the Ca2+/calmodulin-dependent protein kinase-II (CaMKII) to that list. By performing mass spectrometry of heart tissue from wild type mice and CaMKII-null and overexpressing mice, the team identified several different CaMKII phosphorylation sites in the spring elements of titin. They also showed that phosphorylation of titin by CaMKII reduced the passive force, or stiffness, of cardiomyocytes, which would be expected to facilitate heart filling during diastole. But the authors warn that excessive phosphorylation of these sites might be harmful. Indeed, they found that heart tissue from patients with end-stage heart failure exhibited significantly increased phosphorylation at 4 of the 5 CaMKII sites. CaMKII expression and activity were also increased in failing human hearts, consistent with previous reports linking CaMKII upregulation with heart failure. The authors therefore suggest that manipulating phosphorylation of titin at CaMKII sites could help alter myocardial stiffness and improve overall cardiac function in heart failure patients.
- © 2013 American Heart Association, Inc.