Role of RhoA and Rho-associated kinase in phenotypic switching of vascular smooth muscle cells: Implications for vascular function.

Cardiovascular disease (CVD) continues to be the primary cause of global mortality. Vascular smooth muscle cells (VSMCs) are integral components of vascular structure and function, evident by their vital roles in modulating blood flow and pressure. Such roles exist due to the differentiated contractile phenotype of VSMCs. However, VSMCs may switch to a dedifferentiated, proliferative synthetic phenotype in a phenomenon known as phenotypic switching. This switch involves dramatic changes in VSMC migration, proliferation, gene expression programs, differentiation, cellular stiffness and extracellular matrix (ECM) deposition. In this review, we explore the role of the small GTPase Rho and its effector, Rho-associated kinase (ROCK), in phenotypic switching as well as apoptotic pathways in VSMCs. We critically dissect how RhoA promotes cell migration and proliferation as well as its role in modulating the expression of a battery of VSMC marker proteins. We also discuss how RhoA modulates apoptosis, induces dedifferentiation, increases vascular stiffness, or modifies ECM accumulation. These alterations in VSMC phenotypes contribute to multiple vascular dysfunctions, including hypertension and atherosclerosis. Understanding the molecular underpinnings and the signaling pathways involved in these altered phenotypes may provide novel avenues of drug design and other therapeutic interventions for the management of CVDs.

A novel radical prostatectomy specific index (PSI) for the prediction of major cardiovascular events following surgery.

PURPOSE: Prostate cancer patients tend to be older with multiple comorbidities and are thus at increased risk for postoperative cardiovascular events after radical prostatectomy (RP). Thus, proper patient selection strategies are essential to decide for or against a surgical approach. We aimed to derive a prostatectomy specific index (PSI) for patients undergoing RP and compare its performance to universally used indices. METHODS: The cohort was derived from National Surgical Quality Improvement Program database between 2005 and 2012. The primary outcome was incidence of major adverse cardiovascular events at 30 days post-surgery including: death, myocardial infarction, or stroke. A multivariable logistic regression model was constructed, performance and calibration were evaluated using a ROC analysis and the Hosmer-Lemeshow test, the PSI index was derived and compared to the RCRI and AUB-HAS2 indices. RESULTS: A total of 17,299 patients were included in our cohort, with a mean age of 62 ± 7.4 years. Seventy three patients had a cardiac event post RP. The final PSI index encompassed six variables: history of heart disease, age, anemia, American society of anesthesiology class, surgical approach, and hypertension. The PSI ROC analysis provided C-statistic = 0.72, calibration R2 = 0.99 and proper goodness of fit. In comparison, the C-statistics of RCRI and AUB-HAS2 were found to be 0.57 and 0.65, respectively (p value < 0.001). CONCLUSION: The PSI model is a procedure tailored index for prediction of major cardiovascular events post RP. It was calibrated using a large national database aiming to optimize treatment selection strategies for prostate cancer patients.