The Iris Jaffe Lab

Research Publications Cell Biology

 

Aldosterone and the Mineralocorticoid Receptor in Cardiovascular Disease

The Jaffe lab is focused on understanding the role of the hormone aldosterone and it’s receptor, the mineralocorticoid receptor (MR), in the molecular mechanisms of cardiovascular disease. The steroid hormone aldosterone is the final step in the Renin-Angiotensin-Aldosterone pathway that regulates blood pressure and electrolyte homeostasis by activating MR in the kidney to regulate genes involved in renal sodium handling. We and others have recently demonstrated that MR is expressed in cells of the human blood vessel supporting the possibility that direct effects of aldosterone on the vasculature could play a role in vascular function and disease. This is clinically significant because in human clinical trials, pharmacologic inhibition of the MR prevents heart attacks, strokes, and cardiovascular deaths with minimal effects on systemic blood pressure.  We are exploring the molecular mechanisms for these clinical findings in order to gain a better understanding of the mechanisms of cardiovascular disease and to identify novel therapeutic drug targets for common vascular diseases.

MR Regulates Gene Expression in Vascular Cells

We have demonstrated that MR is expressed in human vascular cells where it acts as a ligand-activated transcription factor to regulate gene expression in response to the hormone aldosterone.  In human vascular smooth muscle cells, we have found that MR regulates genes involved in vascular fibrosis and calcification.

Jaffe Fig 1 

Figure 1. Model of MR activation in human vascular cells. Mineralocorticoid receptor (MR) localizes to the nucleus and activates gene transcription in response to aldosterone or angiotensin II (Ang II) treatment. Ang II acts through the type 1 angiotensin receptor (AT1). Aldosterone stimulates mRNA expression of several genes involved in vascular fibrosis, calcification,and inflammation in human VSMCs, including: the parathyroid hormone receptor (PTHR), bone morphogenic protein 2(BMP2), bone-liver-kidney alkaline phosphatase (AlkPhos),interleukin-16(IL-16), and cytotoxic T-lymphocyte–associated protein 4 (CTLA4). This figure is taken from Jaffe and Mendelsohn, 2005  Abstract in PubMed.

We have also studied the function of MR in human endothelial cells (EC).  In these cells, MR regulates genes involved in oxidative stress and inflammation.

Jaffe Fig 2

Figure 2. MR activation in human vascular endothelial cells. In these cells,  MR localizes to the nucleus and activates gene transcription from a MRE in response to aldosterone treatment. 11 β-hydroxysteroid (11 β-HSD2) is expressed and inactivates cortisol in human ECs. Ligand-independent activation of EC MR by serum promotes basal activation of Intercellular adhesion molecule 1 (ICAM1) expression and aldosterone-activated MR stimulates ICAM1 promoter activity, mRNA transcription, and surface protein expression, resulting in increased EC–monocyte adhesion, an early step in atherosclerosis. This figure is taken from Caprio, et al 2008  Abstract in PubMed

Aldosterone Promotes Vascular Injury and Atherosclerosis in Vivo

In addition to cell-based, molecular studies (Figure 3), the Jaffe lab uses whole animal models of cardiovascular disease to study the effects of aldosterone on the vascular system in vivo (Figure 3). In mouse models of wire-induced vascular injury (Figure 3, left) and atherosclerosis (Figure 3, right), aldosterone enhances vascular cell proliferation and fibrosis and promotes atherosclerotic plaque formation. 

Jaffe Fig 2

Figure 3. Animal models of aldosterone-induced vascular injury and atherosclerosis used in the Jaffe lab to study the in vivo role of MR in vascular function and disease. See the text for more details. 

The Jaffe lab is using state-of–the-art, tissue-specific, inducible transgenic and knock-out mouse models to study the mechanisms of these effects in vivo.  In addition, the role and mechanism by which vascular MR may contribute to the regulation of blood pressure is also being investigated in animal models. 

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