Let-7i Inhibits Cardiac Fibrosis (p 776)
Cardiac fibrosis is a final fate of various cardiovascular diseases, leading to increased ventricular stiffness and heart dysfunction. Activation of the renin–angiotensin–aldosterone system is critical for this process. Angiotensin II, a core multifunctional effector of the renin–angiotensin–aldosterone system, can initiate inflammation and extracellular matrix deposition in the heart. MicroRNAs are a class of small noncoding RNAs that play an important role in cardiac development and diseases. However, microRNAs regulating cardiac fibrosis in early stages of cardiac remodeling are poorly characterized. In this study, we demonstrated that angiotensin II infusion significantly downregulated let-7i in mouse heart at days 3 and 7. Increased let-7i was sufficient to attenuate angiotensin II–induced cardiac inflammation and fibrosis through directly reducing the expression of interleukin-6 and collagens, whereas knockdown of let-7i enhanced these effects in vitro and in vivo. These findings highlight the important role of let-7i in angiotensin II–induced cardiac inflammation and fibrosis and extend the knowledge of the mechanism of cardiac fibrosis for early cardiac remodeling. Our results also provide important information to explore the beneficial effect of targeting let-7i as a new therapeutic approach for the treatment of hypertensive cardiac fibrosis and other diseases.
Phosphodiesterase 3A and Hypertension (p 800)
Hypertension with type E brachydactyly is the first Mendelian form of nonsodium-related hypertension. We suggest that increased phosphodiesterase 3A (PDE3A) activity at various sites could cause all phenotypes of hypertension with type E brachydactyly. Blood pressure increases could result in vascular smooth muscle cells through increased vascular smooth muscle cell proliferation. Furthermore, a less weighty foot on the protein kinase A-mediated brake pedal of myosin light-chain kinase could increase peripheral vascular resistance. Finally, a circuitous route involving the cAMP response element-binding protein could influence parathyroid hormone–related peptide to cause short fingers. We also suggest that increased PDE3A activity could actually help the heart. Hypertension with type E brachydactyly draws our research back to the wall, namely the arteriolar vascular wall, the source of increased peripheral vascular resistance that causes hypertension.
The clinical relevance is underscored by a linkage study and a genome-wide association study that coincide with our locus. This state of affairs obligates us to pursue more basic research. We will use mesenchymal stem cell–derived vascular smooth muscle cells, and iPS cells from patients differentiated into cardiac myocytes. Our targets include the A-kinase anchoring proteins. These proteins are largely unexplored in hypertension-related research. Finally, how can this project be brought forward to translation? We have initiated PDE3A expression studies in Zebrafish and CRISPR-Cas9–based mice that will allow us to pursue these hypotheses in individual tissues further and to also provide models for pharmacological interventions. Our findings suggest that raising cGMP may be better than inhibiting PDE3A. We think that we have a new start to address blood pressure–lowering strategies. Let the best messenger win!
Endothelial MicroRNAs Relevant to Hypertension (p 793)
Evidence for the involvement of microRNAs (miRNAs) in human hypertension remains mostly correlative. Kriegel et al have now taken a new approach to systematically identifying endogenous miRNAs in endothelial cells that regulate mRNAs encoded by genes relevant to hypertension. They began by identifying miRNAs present in cultured human microvascular endothelial cells by performing small RNA deep sequencing. Meanwhile, they compiled a list of genes implicated in human hypertension by genome-wide association studies and member genes of established pathways of endothelial signaling relevant to blood pressure regulation. By cross-referencing the 2 sets of data, they identified nearly 100 predicted miRNA target pairs involving 30 highly abundant miRNAs and 31 protein-coding genes relevant to hypertension. They then tested each of these pairs by inhibiting the 30 miRNAs individually and found that, for 35 of the pairs tested, the hypertension-related, predicted target genes were upregulated when the miRNA was inhibited. The 35 miRNA-target pairs involved several genes implicated in human hypertension by genome-wide association studies as well as genes involved in adrenergic signaling, endothelin signaling, and production of reactive oxygen species. The findings indicate widespread, tonic control of genes relevant to blood pressure regulation by endothelial miRNAs. Each of the validated miRNA-target pairs is a viable hypothesis for a future study further examining the mechanistic role and therapeutic potential of miRNAs in human hypertension.
- © 2015 American Heart Association, Inc.