Abrogation of mitochondrial transcription in smooth muscle cells impairs smooth muscle contractility and vascular tone.

BACKGROUND: Smooth muscle cells (SMC) constitute the major contractile cell population of blood vessels and inner organs. SMC contraction depends on energy provided by adenosine triphosphate (ATP) catabolism, which can be generated through oxidative phosphorylation in mitochondria or by anaerobic glycolysis. Mitochondrial activity may also modulate smooth muscle tone by biotransformation of vasoactive mediators. Here, we study the role of mitochondrial DNA gene expression for vascular function in vivo. METHODS: Since loss of functional mitochondria in SMC may not be compatible with normal development, we generated mice with inducible SMC-specific abrogation of the mitochondrial transcription factor A (Tfam). Deletion of this gene leads to dysfunctional mitochondria and prevents aerobic ATP production in affected cells. RESULTS: Invasive blood pressure monitoring in live animals demonstrated that SMC specific Tfam deletion results in lower blood pressure and a defective blood-pressure response to stress, changes that were not compensated by increased heart rate. The contractility to agonists was reduced in arterial and gastric fundus strips from Tfam-deficient mice. Endothelium-dependent relaxation of arterial strips in response to ACh was also blunted. CONCLUSION: Our data show that mitochondrial function is needed for normal gastric contraction, vascular tone, and maintenance of normal blood pressure.

Chemokines as potential therapeutic targets in atherosclerosis.

Atherosclerosis is a chronic disease with high morbidity and mortality around the globe. It is characterized by chronic inflammation of the vessel wall, which is perpetuated by the continuous migration of cells to and within the atherosclerotic lesion. Chemokines (CK) and chemokine receptors (CKR) together with other chemoattractants and adhesion molecules are major mediators facilitating this process. Many CK/CKR (CC, CX3C and CXC) and other chemoattractants (e.g. leukotrienes) have been implicated in atherogenesis, but only a few have been validated as pathogenic by in vitro assays, in vivo experiments using gene-targeted animal models and genetic studies. Promising attempts are currently made to inhibit CK-dependent cell recruitment to lesion by using neutralizing antibodies, mutant proteins, viral and synthetic inhibitors or receptor antagonists. Some of the therapeutics have already entered clinical trials for other conditions and are about to be tested in human atherosclerosis. However, our limited understanding of the complex CK system and the functional specialization of individual CK/CKR, translatability of animal research into human population, limitations of current imaging techniques and surrogate markers for evaluation of the benefits of potential anti-CK compounds are still hampering therapeutic exploitation of the CK system in atherosclerosis. Hopefully we will be able to solve many of these issues in the near future and use this approach to control atherosclerotic disease in man.