Aldosterone (ALDO) is the final mediator of the renin-angiotensin-aldosterone system (RAAS) and a driver of hypertension and inflammation. RAAS overactivation leads to left heart disease (LHD) which is commonly associated with secondary pulmonary hypertension (Type 2 PH). Dysregulated RAAS components and elevated ALDO levels have been described in patients with Type I pulmonary hypertension (PH), even in the absence of LHD. Hence, ALDO excess may be an unrecognized contributor to PH, potentially via immune cell dysregulation in hearts and lungs.

We induced myocardial infarction (MI) in 8-week old male C57BL/6 mice. After six weeks, MI-mice presented with LHD and Type 2 PH, evidenced by reduced ejection fraction, lung edema, and right ventricular (RV) hypertrophy compared to naïve controls Flow-cytometric analyses revealed a phenotypic switch of reparative Ly6C^lomonocytes towards inflammatory Ly6C^himonocytes in the blood and lungs of MI mice. To test for the role of ALDO in PH-LHD, we performed bilateral adrenalectomy (ADX) one week before MI induction, resulting in an absence of systemic ALDO. ADX rescued the MI-induced shift towards Ly6C^himonocytes and resulted in greater numbers of reparative Ly6C^lomonocytes compared to MI mice with regular ALDO plasma levels, demonstrating ALDO-directed programming of monocyte subsets. In line, treatment with the ALDO antagonist spironolactone (SPIRO) resulted in higher Ly6C^lomonocyte counts in blood and lungs of MI-mice compared to vehicle-treated controls. Moreover, SPIRO treatment alleviated histologically assessed lung vascular maladaptation, lung edema, and RV hypertrophy compared to controls, while the underlying LHD was comparable between both groups.

Viewed together, our data suggest that ALDO-directed phenotypic programming of immune cells, particularly monocytes, is a so far unrecognized driver of lung vascular inflammation that may mediate ALDO-dependent lung vascular remodeling and RV dysfunction. Our data provide evidence that ALDO blockage presents a potential strategy for therapeutic intervention in PH.