Training Underrepresented Early-Career Faculty in Cardiovascular Health Research during COVID-19: Structural Inequities and Health Disparity.

The COVID-19 pandemic has highlighted race-based health disparities and structural racism in the United States. Enhancing the training of early-career academic and health scientists from underrepresented minority groups (URM) is critical to reduce disparities affecting underserved population groups. A dedicated training program that has been proven to support URM can facilitate career development for junior faculty during the pandemic. This critical support ensures the retention of talented, racially diverse junior faculty who are poised to mitigate structural racism, rather than perpetuate it. We describe how the Cardiovascular Disease Programs to Increase Diversity Among Individuals Engaged in Health-Related Research (PRIDE-CVD) summer institute successfully transitioned from a face-to-face format to a virtual format during the COVID-19 pandemic. As a result, early-career faculty continued to receive the PRIDE-CVD training on research methodology, grantsmanship, career development, and CVD health disparities, especially as related to the pandemic. In addition, the virtual format facilitated networking, promoted mental wellness, and allowed continual mentorship. Collectively, the program provided timely and relevant career development in the COVID-19 era and helped participants navigate the psychosocial challenges of being a URM in cardiovascular health research.

Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway.

The Phospholipase D (PLD) superfamily is linked to neurological disease, cancer, and fertility, and a recent report correlated a potential loss-of-function PLD2 polymorphism with hypotension. Surprisingly, PLD2 -/- mice exhibit elevated blood pressure accompanied by associated changes in cardiac performance and molecular markers, but do not have findings consistent with the metabolic syndrome. Instead, expression of endothelial nitric oxide synthase (eNOS), which generates the potent vasodilator nitric oxide (NO), is decreased. An eNOS inhibitor phenocopied PLD2 loss and had no further effect on PLD2 -/- mice, confirming the functional relationship. Using a human endothelial cell line, PLD2 loss of function was shown to lower intracellular free cholesterol, causing upregulation of HMG Co-A reductase, the rate-limiting enzyme in cholesterol synthesis. HMG Co-A reductase negatively regulates eNOS, and the PLD2-deficiency phenotype of decreased eNOS expression and activity could be rescued by cholesterol supplementation and HMG Co-A reductase inhibition. Together, these findings identify a novel pathway through which the lipid signaling enzyme PLD2 regulates blood pressure, creating implications for on-going therapeutic development of PLD small molecule inhibitors. Finally, we show that the human PLD2 polymorphism does not trigger eNOS loss, but rather creates another effect, suggesting altered functioning for the allele.

Physiological and pathophysiological roles for phospholipase D.

Individual members of the mammalian phospholipase D (PLD) superfamily undertake roles that extend from generating the second messenger signaling lipid, phosphatidic acid, through hydrolysis of the membrane phospholipid, phosphatidylcholine, to functioning as an endonuclease to generate small RNAs and facilitating membrane vesicle trafficking through seemingly nonenzymatic mechanisms. With recent advances in genome-wide association studies, RNA interference screens, next-generation sequencing approaches, and phenotypic analyses of knockout mice, roles for PLD family members are being uncovered in autoimmune, infectious neurodegenerative, and cardiovascular disease, as well as in cancer. Some of these disease settings pose opportunities for small molecule inhibitory therapeutics, which are currently in development.