Mutations in Phosphodiesterase 3A (PDE3A) Cause Hypertension Without Cardiac Damage

Hypertension with brachydactyly (HTNB) represents an autosomal dominant form of hypertension. It is a rare syndrome, in which the blood pressure can rise by more than 50 mmHg. If untreated, the patients die of stroke by the age of 50 years. In HTNB, vascular smooth muscle cell proliferation is increased, vasodilation compromised, and the kidney not affected. Surprisingly, after decades of hypertension, HTNB is not associated with hypertension-induced cardiac damage. HTNB is caused by gain-of-function mutations in the PDE3A (phosphodiesterase 3A) gene. The mutant enzymes are hyperactive. PDE3A (phosphodiesterase 3A) hydrolyzes and thereby terminates cyclic adenosine monophosphate signaling in defined cellular compartments. The cardioprotective effect involves local changes of cyclic adenosine monophosphate signaling and inhibition of Ca2+ reuptake into the sarcoplasmic reticulum of cardiac myocytes. This review introduces HTNB and discusses how insight into the molecular mechanisms underlying HTNB could contribute to a better understanding of blood pressure control and lead to PDE3A-directed strategies for the treatment of essential hypertension and the prevention of hypertension-induced cardiac damage. A focus will be on cAMP (cyclic adenosine monophosphate) signaling compartments.

Automated summary

Hypertension with brachydactyly (HTNB) is a rare autosomal dominant form of hypertension characterized by a significant rise in blood pressure. HTNB is caused by gain-of-function mutations in the PDE3A gene, resulting in hyperactive mutant enzymes. Despite decades of hypertension, HTNB is not associated with cardiac damage commonly seen in other hypertensive conditions. The cardioprotective effect of HTNB involves local changes in cAMP signaling and inhibition of Ca2+ reuptake. Understanding the molecular mechanisms underlying HTNB could lead to improved strategies for treating essential hypertension and preventing hypertension-induced cardiac damage.