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

Abstract

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 phosphodiesterase 3A ( PDE3A ) 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 Ca 2+ 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.

Reversal of cardiac and renal damage in a teenager with hypertension: A case report

“… 7 The encoded superactive PDE3A enzymes have dual functions: on the one hand, they increase peripheral vascular resistance and cause hypertension through vascular smooth muscle; on the other hand, through cardiomyocytes, they protect against heart damage caused by hypertension. 8 Animal model data also suggest that the PDE3A mutations did not affect the kidney, cause proteinuria, or perturb renal function in the mutant animals. 6 Thus, the transgenic mouse models resemble patients, who aside from stroke also had little evidence of target‐organ damage, and hardly deviate from values observed in patients with essential hypertension.…”

Hypertension and Brachydactyly Syndrome

“…Patients with HTNB are at an increased risk of death by stroke before the 50 years of age if their HTN remains untreated. 1 , 5 , 6 Early identification of HTN in patients with HTNB is critical as timely intervention with antihypertensive medications can mitigate the risks of stroke and hypertension-related organ damage. 5 , 6 Considering that HTNB is attributed to a gain of function mutation in the PDE3A gene, it is plausible that inhibition of PDE3 in individuals with HTNB may be beneficial.…”

“… 1 , 5 , 6 Early identification of HTN in patients with HTNB is critical as timely intervention with antihypertensive medications can mitigate the risks of stroke and hypertension-related organ damage. 5 , 6 Considering that HTNB is attributed to a gain of function mutation in the PDE3A gene, it is plausible that inhibition of PDE3 in individuals with HTNB may be beneficial. Therefore, there is a need to investigate the role of phosphodiesterase-3 inhibitors such as dipyridamole in the management of HTNB.…”