Scientific Gap: Within the cardiovascular system, primary cilia are mechanosensory organelles to detect blood flow and pressure1. Previous proteomic study from primary cilia shows differential expressions of Progesterone receptor component-2 (PGRMC2) in normal vs. abnormal hearts2, 3. The challenge in our studies is that nothing was known about PGRMC2 functions in the heart, which was a major knowledge gap. PGRMC2 is a progesterone receptor. Unlike other progesterone receptors which are involved in a slow effect associated with the gene expressions, PGRMC2 mediates a rapid cellular effect4, 5.
Key Finding: We spent the past four years to understand the roles of PGRMC2. A normal heart is required to regulate its own pressure and volume in each heartbeat. It turns out that PGRMC2 has a very important role in regulating pressure and volume in the heart. For example, under hypoxia which requires the heart to auto-regulate its function, the heart without PGRMC2 fails to control the cardiac pressure and volume. This results in congestive heart failure. Our studies were performed with the cardiac magnetic resonance (CMR) imaging in vivo. To rule out neuronal effect, the CMR results were validated in the “working heart” system, where the heart was isolated, perfused, and challenged with different stresses ex vivo. Both studies confirmed the important role of PGRMC2 as a pressure-volume regulator in the heart.
Specific Discovery: In response to chronic hypoxia, the heart undergoes a series of functional adaptations designed to maintain homeostasis. These changes are vital for protecting both the right and left ventricles, especially under conditions where the heart faces an increased workload6. These adaptive mechanisms are essential for ensuring the heart can continue to perform efficiently, even when subjected to the stress of oxygen deprivation.
To better understand the roles of PGRMC2 in the heart, mice without PGRMC2 were exposed to a hypoxic environment with oxygen levels set at 10% and compared their responses with those in normoxic conditions, where oxygen levels were at 21%. This approach allowed us to examine the specific roles PGRMC2 during periods of cardiac stress, providing valuable insights into how PGRMC2 contributes to the heart's adaptations under stress.
To explore how PGRMC2 plays a role in the heart’s response to oxygen deprivation, we used venous blood gas analyses to compare the reactions of mice with and without PGRMC2 in cardiac myocytes in both normoxic and hypoxic environments. The results were striking. We observed a significant drop in blood pH compared in the hypoxic mice without PGRMC2. This decrease was followed by a notable reduction in base excess levels and bicarbonate concentration, pointing to a clear case of metabolic acidosis. Essentially, the mice were struggling to maintain balance in their blood chemistry under low oxygen conditions. These findings suggest that PGRMC2 may play a crucial role in the heart’s ability to adapt to oxygen deprivation, a crucial role that we were just beginning to resolve.
Exercise also serves as a powerful tool to unmask a subtle cardiac dysfunction that often remains hidden under resting conditions7. To explore the physiological impact of PGRMC2 on cardiac performance, mice were challenged with a treadmill-based exercise test, a widely accepted method for assessing cardiovascular function. Our results revealed a noticeable difference. Compared to their healthy counterparts, mice without PGRMC2 in the hearts failed to run at a longer time or at a same running speed. The physiological impairments in both hypoxia and exercise highlight that cardiac PGRMC2 was essential for maintaining exercise capacity in low-oxygen environments.
The CMR imaging has become an invaluable tool for doctors, offering a non-invasive way to evaluate both the structure and function of the heart. In our research, we thus set out to explore PGRMC2 role in a mouse model using CMR imaging. Mice without cardiac PGRMC2, especially those in hypoxia, showed serious complications as the cardiac failure progressed. Both the right and left sides of the heart struggled to keep up, leading to a condition known as congestive heart failure. This overload of pressure caused blood to back up into the lungs and liver, triggering pulmonary edema, liver congestion, and even abdominal ascites - all while the body was deprived of oxygen.
PGRMC2 is a steroid hormone mediator8, and steroid hormones have long been known to regulate myocardial intracellular calcium levels. The question becomes: can these hormones influence calcium levels through a rapid, non-genomic mechanism, bypassing the traditional receptors? This led us to investigate whether a steroid hormone mediator, PGRMC2, could be a missing link in the rapid calcium responses in cardiomyocytes. To explore this, we tested estradiol, progesterone, and hydrocortisone, three key hormones that might activate PGRMC2. Surprisingly, the steroid hormones didn’t provoke any response in heart myocyte cells without PGRMC2. However, there was a marked increase in cytosolic calcium following steroid hormone exposure when PGRMC2 was re-expressed in those heart cells. This suggests that for a rapid calcium response in cardiomyocytes, particularly under stress conditions like hypoxia, the activation of PGRMC2 is essential.
In conclusion, our study underscores the importance of PGRMC2 in maintaining balanced intracellular signaling, especially in response to steroid hormones. Whether in normal or low-oxygen conditions, PGRMC2 appears to be a critical player in regulating cardiac pressure and volume. This adds a new layer to our understanding of how steroid hormones influence cardiac function through rapid signaling pathways is involved in cardiac pressure-volume regulation.
References
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